EP1370546A2 - Novel amines as histamine-3 receptor ligands and their therapeutic applications - Google Patents

Novel amines as histamine-3 receptor ligands and their therapeutic applications

Info

Publication number
EP1370546A2
EP1370546A2 EP02715079A EP02715079A EP1370546A2 EP 1370546 A2 EP1370546 A2 EP 1370546A2 EP 02715079 A EP02715079 A EP 02715079A EP 02715079 A EP02715079 A EP 02715079A EP 1370546 A2 EP1370546 A2 EP 1370546A2
Authority
EP
European Patent Office
Prior art keywords
pyrrolidinyl
methyl
ethyl
benzofuran
group
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02715079A
Other languages
German (de)
English (en)
French (fr)
Inventor
Marlon D. Cowart
Youssef L. Bennani
Ramin Faghih
Gregory A. Gfesser
Lawrence A. Black
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AbbVie Inc
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/810,648 external-priority patent/US20020177589A1/en
Priority claimed from US10/044,495 external-priority patent/US20020183309A1/en
Priority claimed from US10/081,207 external-priority patent/US6969730B2/en
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to EP10180385A priority Critical patent/EP2258694A1/en
Publication of EP1370546A2 publication Critical patent/EP1370546A2/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • TECHNICAL FIELD This invention relates to compounds useful for treating diseases or conditions caused by or exacerbated by histamine-3 receptor activity, pharmaceutical compositions containing such compounds and methods of treatment using such compounds.
  • Histamine is a well-known mediator in hypersensitive reactions (e.g. allergies, hay fever, and asthma) which are commonly treated with antagonists of histamine or "antihistamines.” It has also been established that histamine receptors exist in at least two distinct types, referred to as Hi and H 2 receptors.
  • H 3 receptor A third histamine receptor (H 3 receptor) is believed to play a role in neurotransmission in the central nervous system, where the H 3 receptor is thought to be disposed presynaptically on histaminergic nerve endings (Nature, 302, 832-837 (1983)).
  • the existence of the H 3 receptor has been confirmed by the development of selective H 3 receptor agonists and antagonists (Nature, 327, 117-123 (1987)) and has subsequently been shown to regulate the release of other neurotransmitters in both the central nervous system and peripheral organs, particularly the lungs, cardiovascular system and gastrointestinal tract.
  • a number of diseases or conditions may be treated with histamine-3 receptor ligands wherein the H 3 ligand may be an antagonist, agonist or partial agonist.
  • diseases or conditions include cardiovascular disorders such as acute myocardial infarction; memory processes, dementia and cognition disorders such as Alzheimer's disease and attention-deficit hyperactivity disorder; neurological disorders such as Parkinson's disease, schizophrenia, depression, epilepsy, and seizures or convulsions; cancer such as cutaneous carcinoma, medullary thyroid carcinoma and melanoma; allergic rhinitis; respiratory disorders such as asthma; sleep disorders such as narcolepsy; vestibular dysfunction such as Meniere's disease; gastrointestinal disorders, inflammation, migraine, motion sickness, obesity, pain, and septic shock.
  • A is selected from carbonyl or a covalent bond
  • D is selected from O or S
  • L is selected from lower alkylene, fluoroalkylene, or hydroxyalkylene
  • Ri and R 2 are each independently selected from hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl, alkenyl, or alkynyl; or
  • R 3 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, -NRAR B , (NR A R B )alkyl, (NR A R B )carbonyl, or (NR A R B )sulfonyl;
  • R-j, R 5 , Re and R are each independently selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, formyl, halogen, haloalkoxy, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, (NR A R B )sulfonyl, -L 2 R 20 , or -R 2 oL 3 R 22 ;
  • R 2 o is selected from aryl, heterocycle, or cycloalkyl;
  • R ⁇ is selected from hydrogen or alkyl
  • R 2 2 is selected from aryl, heterocycle, or cycloalkyl
  • R A and R B are each independently selected from hydrogen, alkyl, alkylcarbonyl or formyl; provided that at least one of R 4 , R 5 , Rg, or R 7 is aryl, heterocycle, cycloalkyl, -L 2 R 2 o or -R2oL 3 R 22 .
  • the compounds can be incorporated into pharmaceutical compositions and can be useful in methods for treating or preventing disorders related to histamine-3 receptor modulation.
  • the compounds, compositions comprising the compounds, and methods for treating or preventing disorders by administering the compounds are further described herein.
  • the present invention discloses compounds and compositions thereof which are useful for selectively modulating the effects of the histamine-3 receptors in a mammal.
  • the compounds of the invention can be used for treating and preventing disorders modulated by the histamine-3 receptor.
  • the disorders are those that are ameliorated by selectively modulating the histamine-3 receptors in a mammal.
  • One method of the invention provides for treating a disorder selected from acute myocardial infarction, asthma, bipolar disorder, cognitive enhancement, cognitive deficits in psychiatric disorders, cutaneous carcinoma, drug abuse, depression, gastrointestinal disorders, inflammation, jet lag, medullary thyroid carcinoma, melanoma, allergic rhinitis, Meniere's disease, migraine, mood and attention alteration, motion sickness, neurogenic inflammation, obsessive compulsive disorder, pain, Parkinson's disease, schizophrenia, seizures, septic shock, Tourette's syndrome, vertigo, or wakefulness.
  • the method can be particularly useful for treating Alzheimer's disease, attention-deficit hyperactivity disorder, epilepsy, narcolepsy, and cognitive and memory-related disorders, for example, mild cognitive impairment, deficits of memory, and deficits of learning and dementia.
  • alkenyl refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens.
  • alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5- hexenyl, 2-heptenyl, 2-methyl-l-heptenyl, and 3-decenyl.
  • alkenylene means a divalent group derived from a straight or branched chain hydrocarbon of from 2 to 10 carbon atoms containing at least one double bond.
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkoxyalkyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of alkoxyalkyl include, but are not limited to, tert-butoxymethyl, 2- ethoxyethyl, 2-methoxyethyl and methoxymethyl.
  • alkoxycarbonyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl.
  • alkyl refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl and n-decyl.
  • alkylcarbonyl refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-l-oxopropyl, 1 -oxobutyl and 1-oxopentyl.
  • alkylcarbonyloxy refers to an alkylcarbonyl group, as defined herein, appended to the parent molecular moiety through an oxy moiety, as defined herein.
  • Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy and tert-butylcarbonyloxy.
  • alkylene means a divalent group derived from a straight or branched chain hydrocarbon of from 1 to 10 carbon atoms.
  • Representative examples of alkylene include, but are not limited to, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and -CH 2 CH(CH 3 )CH 2 -.
  • alkylsulfinyl refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfinyl group, as defined herein.
  • Representative examples of alkylsulfinyl include, but are not limited to, methylsulfinyl and ethylsulfinyl.
  • alkylsulfonyl refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of alkylsulfonyl include, but are not limited to, ethylsulfonyl, isopropylsulfonyl and methylsulfonyl.
  • alkylthio refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a sufur atom, as defined herein.
  • Representative examples of alkylthio include, but are not limited to, methylsulfanyl, ethylsulfanyl, tert-butylsulfanyl and hexylsulfanyl.
  • aryl refers to a monocyclic-ring system, or a bicyclic- or a tricyclic- fused ring system wherein one or more of the fused rings are aromatic.
  • Representative examples of aryl include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
  • the aryl groups of this invention are substituted with 0, 1, 2, 3, 4 or 5 substituents independently selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, oximyl, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, and (NR A R B )sulfonyl.
  • arylalkyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3- phenylpropyl, and 2-naphth-2-ylethyl.
  • arylcarbonyl refers to an aryl group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • arylcarbonyl include, but are not limited to, benzoyl, phenylacetyl, 3-chlorophenylacetyl, 3-methoxyphenylacetyl, 4-fiuoro-3-methylphenylacetyl, 3-phenylpropionyl, and 2-naphthylacetyl.
  • carbonyl refers to a -C(O)- group.
  • carboxyalkyl refers to a carboxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2- carboxyethyl, and 3-carboxypropyl.
  • cyano refers to a -CN group.
  • cyanoalkyl refers to a cyano group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cyanoalkyl include, but are not limited to, cyanomethyl, 2- cyanoethyl and 3-cyanopropyl.
  • cycloalkyl refers to a saturated cyclic hydrocarbon group containing from 3 to 8 carbons.
  • examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl .
  • cycloalkylalkyl refers to cycloalkyl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl and 4-cycloheptylbutyl.
  • fluoroalkylene means an alkylene, as defined herein, containing 1 or fluorine atoms.
  • Representative examples of fluoroalkylene include, but are not limited to, -CH 2 CH(F)-, -CH 2 C(F) 2 -, -CH 2 C(F) 2 CH 2 -, and -CH 2 CH 2 C(F) 2 -.
  • halo or halogen, refers to -CI, -Br, -I or -F.
  • haloalkoxy refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkoxy group, as defined herein.
  • Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2- fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy.
  • haloalkyl refers to at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, fluoromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
  • heterocycle refers to a monocyclic or bicyclic ring system.
  • Monocyclic ring systems are exemplified by any 3- or 4-membered ring containing a heteroatom independently selected from oxygen, nitrogen and sulfur; or a 5-, 6-, or 7-membered ring containing one, two or three heteroatoms wherein the heteroatoms are independently selected from nitrogen, oxygen and sulfur.
  • the 5-membered ring has from 0-2 double bonds and the 6- and 7-membered rings have from 0-3 double bonds.
  • monocyclic ring systems include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepinyl, 1,3-dioxolanyl, dioxanyl, dithianyl, furyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl,
  • example of monocyclic ring systems can include, but are not limited to, 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2 -methyl- 1 -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- dimethylpyrrolidinyl, 1 -pyrrolidinyl, 2-methyl-l -pyr
  • Bicyclic ring systems are exemplified by any of the above monocyclic heterocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic heterocyclic ring system.
  • bicyclic ring systems include but are not limited to, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, benzopyranyl, benzothiopyranyl, benzodioxinyl, 1,3-benzodioxolyl, cinnolinyl, indazolyl, indolyl, indolinyl, indolizinyl, naphthyridinyl, 3H-imidazo[4,5-c]pyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoindolinyl, isoquinolinyl, phthalazinyl, pyranopyridyl, quinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, tetrahydroisoquinolinyl, tetrahydroquinolin
  • heterocycles of this invention are substituted with 0, 1, 2, or 3 substituents independently selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, arylalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, haloalkylcarbonyl, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl and (NR A R B )sulfonyl.
  • heterocyclealkyl refers to a heterocycle, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heterocyclealkyl include, but are not limited to, pyridin-3- ylmethyl and 2-pyrimidin-2-ylpropyl.
  • heterocyclecarbonyl refers to a heterocycle, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of heterocyclecarbonyl include, but are not limited to, lH-imidazol- 1 -ylcarbonyl, 4-mo ⁇ holinylcarbonyl, 1-piperidinylcarbonyl and cyclopentylaminocarbonyl.
  • hydroxy refers to an -OH group.
  • hydroxyalkyl refers to one or two hydroxy groups, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypro ⁇ yl and 2-ethyl-4- hydroxyheptyl.
  • hydroxyalkylene means an alkylene, as defined herein, containing 1 or hydroxy groups.
  • Representative examples of hydroxyalkylene include, but are not limited to, -CH 2 CH(OH)-, -CH 2 CH(OH)CH 2 -, -CH 2 CH 2 CH(OH)-, and -CH 2 CH(OH)CH(OH)-.
  • lower alkylene is a subset of alkylene as defined herein and means a straight or branched chain hydrocarbon group containing from 1 to 6 carbon atoms.
  • Representative examples of lower alkylene are -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, and -CH 2 CH 2 CH 2 CH .
  • mercapto refers to a -SH group.
  • nitro refers to a -NO 2 group.
  • -NR A R B refers to two groups, R A and R B , which are appended to the parent molecular moiety through a nitrogen atom.
  • R A and R B are each independently selected from hydrogen, alkoxy, alkyl, alkylcarbonyl, and formyl.
  • Representative examples of -NR A R B include, but are not limited to, acetylamino, amino, formylamino, dimethylamino, and methylamino.
  • (NR A R B )alkyl refers to a -NR A R ⁇ group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of (NR A R ⁇ )alkyl include, but are not limited to, (amino)methyl, (dimethylamino)methyl and (ethylamino)methyl.
  • (NR A R B )carbonyl refers to a -NR A R B group, as defined herein, appended to the parent molecular moiety through a carbonyl group, as defined herein.
  • Representative examples of (NR A RB)carbonyl include, but are not limited to, aminocarbonyl, dimethylaminocarbonyl and ethylaminocarbonyl.
  • (NR A RB)sulfonyl refers to an amino group, as defined herein, appended to the parent molecular moiety through a sulfonyl group, as defined herein.
  • Representative examples of aminosulfonyl include, but are not limited to, aminosulfonyl, dimethylaminosulfonyl and ethylaminosulfonyl.
  • oximyl refers to a group wherein R 99 and Rioo are independently selected from hydrogen and alkyl.
  • oxy refers to a -O- moiety.
  • sulfinyl refers to a -S(O)- group.
  • sulfonyl refers to a -SO2- group.
  • Compounds of the present invention include at least those compounds of formula (I) wherein one substituent represented by R , R 5 , R 6 or R 7 are selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aryl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, formyl, halogen, haloalkoxy, haloalkyl, heterocycle, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, (NR A R B )sulfonyl, -L 2 R 2 o, or -R20L3R22.
  • R , R 5 , R 6 or R 7 are selected from hydrogen, alk
  • R4, R5, Re and R 7 is selected from hydrogen or alkyl.
  • Particular groups for the substituents represented by R ⁇ R 5 , Re and R can be selected from hydrogen, alkyl, heterocycle, -L 2 R 2 o, and -R20L3R22.
  • Compounds of the present invention also can have the formula (I) wherein A is a covalent bond; D is O; L is -CH2CH2-; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached form heterocycle; R 3 , R , R 5 , and R are hydrogen; and R$ is L 2 R20.
  • Heterocycles formed by R ⁇ and R 2 can include, but are not limited to, azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl. (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl.
  • Particular examples of heterocycles for compounds of the invention are, for example, 1-azepanyl, (3S)-3-
  • the (2R)-2-methyl-l -pyrrolidinyl group may be preferred.
  • Groups for R 6 can include, but are not limited to, a group represented by the formula L 2 R 20 , alkylcarbonyl, heterocycle, or a group represented by R 2 oL 3 R 22 .
  • R ⁇ is L2R20
  • R 2 0 include, but are not limited to, phenyl that is substituted with 0, 1, 2 or 3 substituents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NR A R B )carbonyl, or NR A R ⁇ .
  • substituents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NR A R B )carbonyl, or NR A R ⁇ .
  • Heterocycle groups suitable for R ⁇ are, for example, furyl, imidazolyl, isothiazolyl, isothiazolinyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl, triazolyl, benzimidazolyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzofuranyl, cinnolinyl, indazolyl, indolyl, indolizinyl, naphthyridinyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, quinolinyl, quino
  • the heterocycle group for R 6 is substituted with 0, 1 , 2 or 3 substituents selected from alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, arylalkyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, haloalkylcarbonyl, hydroxy, hydroxyalkyl, mercapto, nitro, oxo, -NR A R B , (NR A R ⁇ )alkyl, (NR A R B )carbonyl and (NR A R B )sulfonyl; wherein R A and R B are as defined in formula (I).
  • heterocycles for Rg are l,2,4-oxadiazol-3-yl, 3-pyridinyl, 4-isoxazolyl and lH-imidazol-1-yl, wherein the heterocycle is substituted with 0, 1 or 2 substituents selected from hydrogen, alkyl, haloalkyl, or hydroxyalkyl.
  • Phenyl groups are particularly suitable for an aryl group R 22 .
  • Such phenyl groups is substituted with 0, 1, 2 or 3 substituents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NR A R B )carbonyl, and NR A R B .
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH 2 -; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3 R)-3 -hydroxy- 1 -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl,
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; R t and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R ⁇ R 5 and R are hydrogen; R ⁇ is L-R 2 0. L 2 is selected from alkylene and al
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1-azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3 R)-3 -hydroxy- 1 -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2R)-3-
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R 3 , R ⁇ R 5 and R 7 are hydrogen; and R 6 is L 2 R 20 ; L 2 is selected from alkylene and alkenylene; and R20 is phenyl substituted with 0, 1 , 2, or 3 substituents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NR A R B )carbonyl, or -NR A R B .
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1 -dioxidothiomo ⁇ ho.inyl; R 3) R- t , R 5 and R are hydrogen; and R ⁇ is alkylcarbonyl.
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3 R)-3 -hydroxy- 1 -pyrrolidinyl, (3S)-3- hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2 -methyl- 1 -pyrrolidinyl; R 3 , R-(, R s and R are hydrogen; and Re is alkylcarbonyl.
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl- 1 -pyrrolidinyl, 2,5-dihydro- 1 H-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R- ⁇ , R 5 and R 7 are hydrogen; and R ⁇ is heterocycle.
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1-azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3 R)-3 -hydroxy- 1 -pyrrolidinyl, (3S)-3- hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R 4 , R 5 and R are hydrogen; Re is a heterocycle selected from furyl, imidazolyl, iso
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R 3 , R- t , R 5 and R 7 are hydrogen; and R 6 is a heterocycle selected from l,2,4-oxadiazol-3-yl, 3-pyridinyl, 4-isoxazolyl, or lH-imidazol-1- yl wherein the heterocycle is substituted with 0, 1, or 2 substituents selected from hydrogen, alkyl, haloalkyl, or hydroxyalkyl.
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R 4 , R 5 and R are hydrogen; Re is -R 2 oL 3 R 22 ; R 2 0 is
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R 3 , R-,, R 5 and R 7 are hydrogen; R is -R 2 oL 3 R 22 ; R20 is l,2,4-oxadiazol-3-yl; L 3 is selected from a covalent bond and alkylene; and R 22 is phenyl substituted with 0, 1, 2, or 3 substitutents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, alkylthio, carboxy, cyano, formyl, haloalkoxy, haloalkyl, halogen, hydroxyalkyl, oximyl, (NR A R B )carbony
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R-i, R 5 and R are hydrogen; Re is -R2oL 3 R 22 ; R 2 0 is
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1-azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l-pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethy -piperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l-pyrrolidinyl; R 3 , R 4 , R 5 and R 7 are hydrogen; Re is -R 2 oL 3 R 22 ; R20 is l,2,4-oxadiazol-3-yl; L 3 is selected from a covalent bond and alkylene; and R 22 is 2- thienyl.
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH2CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R 4 , R 5 and R are hydrogen; R is -R20L3R22; R20 is aryl; L
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1-azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l -pyrrolidinyl, (3S)-3- hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2R
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R , R 5 and R are hydrogen; Re is -R 2 oL 3 R 22 ; R 2 o is
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3 -hydroxy- 1 -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl,
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R 4 , R 5 and R 7 are hydrogen; Re is -R2oL 3 R 22 ; R 20 is
  • compounds of the present invention have formula (I) wherein A is a covalent bond; D is O; L is -CH 2 CH 2 -; P and Q taken together form a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3- (dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l -pyrrolidinyl, (3S)-3- hydroxy-1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2- (hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2- methyl-1 -piperidinyl, 1 -piperidinyl, (2
  • compounds of the present invention have formula (II) (II), or a pharmaceutical acceptable salt, ester, amide, or prodrug thereof, wherein
  • R is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, or (NR A R B )sulfonyl;
  • R 8 is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl, or (NR A R B )carbonyl;
  • R 9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, or (NR A R B )sulfonyl;
  • X is selected from CH, CRx, or N;
  • Y is selected from CH, CR ⁇ ; or N;
  • Z is selected from CH, CRz, or N;
  • Rx, R Y and Rz groups are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, or (NR A R ⁇ )sulfonyl; and A, D, L, R A) R B , R I , R 2 , R3, R , and R5 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; and D, L, R A , R B , Ri, R 2 , R 3 , Rt, R5, R7, R 8 , R9, X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond, Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R is cyano; and D, L, R A , R B , 3, R4, R5, R7 and R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein L is -CH 2 CH 2 -; A is a covalent bond; Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 3 , R , R 5 , R 7 and R 9 are hydrogen; R 8 is cyano; X is CH; Y is CH; Z is CH; and D, R A , and R B are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is cyano; X is N; Y is CH; Z is CH; and D, L, R A , R B , R 3 , R 4 , R 5 , R 7 and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is heterocyclecarbonyl; and D, L, R A , R B , R 3 , R 4 , R 5 , R 7 , R 9 , X, Y and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1- pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4- thiomo ⁇ holinyl, and l,l-dioxidothiomo ⁇ holin-4-yl; and D, L, R A , R B , R 3 , R , R 5 , R 7 , R 9 , X, Y and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is heterocyclecarbonyl wherein the heterocycle is 4-mo ⁇ holinyl; and D, L, R A , R B , R 3 , R 4 , R 5 , R 7 , R 9 , X, Y and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 3 , R-j, R 5 , R and R are hydrogen; R 8 is heterocyclecarbonyl wherein the heterocycle is 4-mo ⁇ holinyl; X is CH; Y is CH; Z is CH; and D, R A and RB are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is heterocyclecarbonyl; X is N; Y is CH; Z is CH; and D, L, R A , R B , R 3 , R», R 5 , R 7 and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; R 8 is heterocyclecarbonyl wherein the heterocycle of heterocarbonyl is selected from the group consisting of azetidinyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl.; X is N; Y is CH; Z is CH; and D, L, R A , R B , R 3 , R-t, R 5 , R 7 and R 9 are as defined in formula (II)
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R ⁇ are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1- pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4- thiomo ⁇ holinyl, and l,l-dioxidothiomo ⁇ holin-4-yl; X is N; Y is CH; Z is CH; and D, L, R A , R B , R 3 , R , R 5 , R 7 and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R] and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R is heterocyclecarbonyl wherein the heterocycle is 4-mo ⁇ holinyl; X is N; Y is CH; Z is CH; and D, L, R A , R B , R 3 , R-i, R5, R7 and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 3 , R , R 5 , R 7 and R 9 are hydrogen; R 8 is heterocyclecarbonyl wherein the heterocycle is 4-mo ⁇ holinyl; X is N; Y is CH; Z is CH; and D, R A and R B are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle and D, L, R A , R B , R 3 , R 4 , R 5 , R 7 , Rg, R , X, Y and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1- dioxidothiomo ⁇ holinyl; R g is cyano; and D, L, R A , R B , R 3 , R ⁇ R 5 ,R 7 , R , X, Y and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5-
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 , R , R 5 , and R are independently selected from hydrogen, alkyl, alkylcarbonyl, and halogen; Rg and R 9 are independently selected from hydrogen, alkoxy
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3 -hydroxy- 1 -pyrrolidinyl, (3S)-3-hydroxy-l -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrol
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle substituted with 0, 1 or 2 substituents selected from alkyl; R 3 , R-i, R 5 , R , and R 9 are hydrogen; R 8 is cyano; X is CH; Y is CH; and Z is CH.
  • compounds of the present invention have formula (II) wherein L is -CH 2 CH 2 -; A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1-dioxidothiomo ⁇ holinyl; R 3 is heterocycle; R-j, R 5 , R and R are hydrogen; R 8 is cyano; X is CH; Y is CH; and Z is CH.
  • compounds of the present invention have formula (II) wherein L is -CH 2 CH 2 -; A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3 -hydroxy- 1 -pyrrolidinyl, (3S)-3-hydroxy-l -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrol
  • compounds of the present invention have formula (II) wherein L is -CH 2 CH 2 -; A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle (2R)-2-methyl-l -pyrrolidinyl; R 3 is heterocycle selected from 2-furyl, 3-pyridinyl, and 2-thienyl wherein the heterocycle is substituted with 0, 1, or 2 substituents selected from hydrogen, alkoxy, alkyl, alkoxycarbonyl, alkylcarbonyl, carboxy, cyano, formyl, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, or oximyl; R , R 5 , R and R 9 are hydrogen; R 8 is cyano; X is CH;Y is CH; and Z is CH.
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; R 8 is cyano; X is N; Y is CH; Z is CH; and D, L, R A , R B , R 3 , R , R5, R7 and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1- dioxidothiomo ⁇ holinyl; R 8 is cyano; X is N; Y is CH; Z is CH; and D, L, R A , R B , R 3 , R 4 , R 5 , R 7 and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; R g is heterocyclecarbonyl; and D, L, R A , R B , R 3 , R , R 5 , R 7 , R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl.
  • R 8 is heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of azetidinyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1 -dioxidothiomo ⁇ holinyl; and D, L, R A , R B , R 3 , R ⁇ R5, R ,
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1 ,1- dioxidothiomo ⁇ holinyl; R 8 is heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridin
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of 1 -azepanyl, (3S)-3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3-hydroxy-l-pyrrolidinyl, (3 S)-3-hydroxy-l -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrolidinyl, (c
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1-azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5-
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1- dioxidothiomo ⁇ holinyl; R 8 is heterocyclecarbonyl wherein the heterocycle is 4-mo ⁇ holinyl; and D, L, R A , R B , R 3 , R-t, R5, R 7 , R 9 , X,
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1 ,1- dioxido thiomo ⁇ holinyl; R 3 , R 4 , R 5 , R 7 and R 9 are hydrogen; R 8 is heterocyclecarbonyl wherein the heterocycle is 4-mo ⁇ holinyl; X is CH; Y is CH; Z is CH;
  • compounds of the present invention have formula (II) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5-
  • compounds of the present invention have formula (II) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; R 8 is heterocyclecarbonyl; X is N; Y is CH; Z is CH; and D, L, R A , R B , R 3 , R ⁇ R 5 , R 7 , and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1 -dioxidothiomo ⁇ holinyl; Rg is heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3-hydroxy-l -pyrrolidinyl, (3 S)-3-hydroxy-l -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrolidin
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl.
  • R 8 is heterocyclecarbonyl wherein the heterocycle is 4-mo ⁇ holinyl;
  • X is N;
  • Y is CH;
  • Z is CH; and
  • D, L, R A , R B , R 3 , R , R 5 ,R 7 , and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3-hydroxy-l -pyrrolidinyl, (3S)-3-hydroxy-l -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrolidin
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1 -dioxidothiomo ⁇ holinyl; R 3 , R , R 5 , R 7 and R 9 are hydrogen; R 8 is heterocyclecarbonyl wherein the heterocycle is 4-mo ⁇ holinyl; X is N;
  • compounds of the present invention have formula (II) wherein A is a covalent bond; L is -CH 2 CH 2 -; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3 -hydroxy- 1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-di
  • compounds of the present invention have formula (II) wherein A is carbonyl; Ri and R 2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and Rg is selected from the group consisting of cyano and heterocyclecarbonyl; and D, L, R A , R B , R 3 , R 4 , R 5 , R 7 , and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is carbonyl; Ri and R 2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; and Rg is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of azetidinyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1 -dioxidothiomo ⁇ holinyl; and D, L, R A , R B , R 3 , R . R 5 , R , and R 9 are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is carbonyl; R ⁇ and R 2 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; Rg is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of 1 -azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1- piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro- l(2H)-pyridinyl, 4-thiomo ⁇ holinyl, and l,l-dioxidothiomo ⁇ holin-4-yl; and D, L, R A , R B , R 3 , R 4 , R5, R 7 ,
  • compounds of the present invention have formula (II) wherein A is carbonyl; and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; R 8 is selected from cyano or heterocyclecarbonyl; and D, L, R A , R B , R3, R 4 , R 5 , R 7 , R 9 , X, Y and Z are as defined in formula (I).
  • compounds of the present invention have formula (II) wherein A is carbonyl; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1- dioxidothiomo ⁇ holinyl; Rg is selected from cyano or heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1 -piperidinyl, 3-
  • compounds of the present invention have formula (II) wherein A is carbonyl; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from the group consisting of azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1 -dioxidothiomo ⁇ holinyl; R 8 is selected from the group consisting of cyano and heterocyclecarbonyl wherein the heterocycle of heterocyclecarbonyl is selected from the group consisting of 1 -azetidinyl, 4-mo ⁇ holiny
  • compounds of the present invention have formula (II) wherein A is carbonyl; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy- 1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2 S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2
  • compounds of the present invention have formula (HI)
  • R 6 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • R 8 is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl or (NR A R B )carbonyl;
  • R 9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • X is selected from CH, CRx or N;
  • Y is selected from CH, CRy or N;
  • Z is selected from CH, CRz or N;
  • Rx, R Y and Rz are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R ⁇ )sulfonyl; and
  • R A , D, L, R A , R B , R I , R 2 , R 3 , R 4 , and R 5 are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is a covalent bond; and D, L, R A , R B , R I , R 2 , R 3 , R , R5, e, R 8 , R9, X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is a covalent bond; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is selected from cyano or heterocyclecarbonyl; and D, L, R A , R B , R3, R-t, R5, Re, R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is a covalent bond; Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl and alkynyl; Rg is selected from cyano or heterocyclecarbonyl wherein the heterocycle is selected from 1 -azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1- piperidinyl, 3-pyridinyl, 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro- l(2H)-pyridinyl, 4-thiomo ⁇ holinyl, and 1 , 1 -dioxidothiomo ⁇ holin-4-yl; D, L, R A , R B , R 3 , Rj, R5, Re, R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; Rg is selected from cyano or heterocyclecarbonyl; and D, L, R A , R B , R 3 , R , R 5 , Re, R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1- dioxidothiomo ⁇ holinyl; R 8 is selected from cyano or heterocyclecarbonyl wherein the heterocycle is selected from 1-azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1 -piperidinyl, 3- pyri
  • compounds of the present invention have formula (III) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5-
  • compounds of the present invention have formula (III) wherein A is carbonyl; and D, L, R A , R B , Ri, R2, R3, R ⁇ t, R5, Re, R 8 , R9, X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is carbonyl; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is cyano; and D, L, R A , RB, R3, R4, R5, R ⁇ , R9, X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein L is -CH 2 CH 2 -; A is carbonyl; Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 3 is methyl, R , R 5 , Re and R 9 are hydrogen; R 8 is cyano; X is CH; Y is CH; Z is CH; and D, R A and R B are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is carbonyl; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; Rg is heterocyclecarbonyl; and D, L, R A , R B , R 3 , R 4 , R 5 , R 6 , R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is carbonyl; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is heterocyclecarbonyl wherein the heterocycle is selected from 1-azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1- pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, 1-pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, 4- thiomo ⁇ holinyl, and 1 , 1 -dioxidothiomo ⁇ holin-4-yl; and D, L, R A , R B , R 3 , R , R 5 , R 6 , R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is carbonyl; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; R 8 is cyano; and D, L, R A , R B , R 3 , R- t , R 5 , Re, R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is carbonyl; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1 ,1- dioxidothiomo ⁇ holinyl; R 8 is cyano; and D, L, R A , R B , R 3 , R.;, R 5 , R 6 , R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is carbonyl; R) and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5-
  • compounds of the present invention have formula (III) wherein L is -CH 2 CH 2 -; A is carbonyl; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l- pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1 -dioxidothiomo ⁇ holinyl; R 3 is methyl; R , R 5 , Re and R 9 are hydrogen; R 8 is cyano; X is CH; Y is CH; Z is CH; and D, L, R A and R
  • compounds of the present invention have formula (III) wherein L is -CH 2 CH 2 -; A is carbonyl; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidiny
  • compounds of the present invention have formula (III) wherein A is carbonyl; Ri and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; Rg is heterocyclecarbonyl; and D, L, R A , R B , R 3 , R 4 , R5, Re, R9, X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (III) wherein A is carbonyl; R ⁇ and R2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1- dioxidothiomo ⁇ holinyl; R 8 is heterocyclecarbonyl wherein the heterocycle is selected from 1-azetidinyl, 4-mo ⁇ holinyl, 1 -piperazinyl, 1 -piperidinyl, 3-pyridinyl, 1
  • compounds of the present invention have formula (III) wherein A is carbonyl; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5
  • R 7 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • R 8 is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl or (NR A R B )carbonyl;
  • R 9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • X is selected from CH, CRx or N;
  • Y is selected from CH, CRy or N;
  • Z is selected from CH, CRz or N;
  • Rx, Ry and Rz are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A , R B , (NR A R ⁇ )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl; and
  • D, L, R A , RB, R I , R 2 , R 3 , R 4 and R 5 are as defined in formula (I).
  • compounds of the present invention have formula (IV) wherein A is a covalent bond; and D, L, R A , R B , R,, R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (IV) wherein A is a covalent bond; Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is cyano; and D, L, R A , R B , R 3 , R 4 , R 5 , R 7 , R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (IV) wherein L is -CH2CH2-; A is a covalent bond; R ⁇ and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 3 , R 4 , R 5 , R 7 and R 9 are hydrogen; R 8 is cyano; X is CH; Y is CH; Z is CH; and D, R A and R B are as defined in formula (I).
  • Re is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • Rg is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl or (NR A R ⁇ )carbonyl;
  • R 9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • X is selected from CH, CRx or N;
  • Y is selected from CH, CR Y or N
  • Z is selected from CH, CR Z or N;
  • Rx, RY and Rz are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl; and A, D, L, R A , R B , Ri, R 2 , R 3 , R , R 5 are as defined in formula (I).
  • compounds of the present invention have formula (V) wherein A is a covalent bond; and D, L, R A , R B , Rj, R 2 , R 3 , i, R 5 , Re, R 8 , R 9 , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (IV) wherein A is a covalent bond; Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 8 is cyano; and D, L, R A , R B , R 3 , ⁇ , R 5 , Re, R , X, Y, and Z are as defined in formula (I).
  • compounds of the present invention have formula (IV) wherein L is -CH 2 CH 2 -; A is a covalent bond; Ri and R 2 are each independently selected from hydrogen, alkyl, hydroxyalkyl, alkenyl or alkynyl; R 3 , R-j, R 5 , Re and R 9 are hydrogen; R is cyano; X is CH; Y is CH; Z is CH; and D, R A and R B are as defined in formula (I).
  • R 5 , Re, and R are selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • R 8 is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl and (NR A R B )carbonyl;
  • R 9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbon
  • X is selected from CH, CRx or N;
  • Y is selected from CH, CRY or N;
  • Z is selected from CH, CRz or N;
  • Rx, R Y and Rz are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R ⁇ , (NR A R ⁇ )alkyl, (NR A R B )carbonyl or (NR A R ⁇ )sulfonyl; and
  • R A , D, L, R A , R B , Ri, R 2 , and R 3 are as defined in formula (I).
  • compounds of the present invention have formula (VI) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; P, Q, D, L, R A , R B , and R 3 , are as defined in formula (I) and R 5 , Re, R 7 , Rg, and R 9 are defined as in formula (VI).
  • compounds of the present invention have formula (VI) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2 -methyl- 1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1- dioxidothiomo ⁇ holinyl; R 8 is cyano; and P, Q, D, L, R A , R B , and R 3 , are as defined in formula (I) and R 5 , Re, R 7 , and R 9 are defined as in formula (VI).
  • compounds of the present invention have formula (VI) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,5- di
  • compounds of the present invention have formula (VI) wherein L is -CH 2 CH 2 -; A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1 , 1 -dioxidothiomo ⁇ holinyl; R 3 , R 5 , R ⁇ , R and R 9 are hydrogen; Rg is cyano; X is CH;Y is CH; and Z is CH.
  • compounds of the present invention have formula (VI) wherein L is -CH 2 CH 2 -; A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3 -hydroxy- 1 -pyrrolidinyl, (3S)-3-hydroxy-l-pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyrrol
  • compounds of the present invention have formula (VII) (VII), or a pharmaceutical acceptable salt, ester, amide, or prodrug thereof, wherein
  • R ⁇ R 6 , and R 7 are selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, -NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • Rg is selected from hydrogen, alkylcarbonyl, arylcarbonyl, cyano, cycloalkylcarbonyl, heterocyclecarbonyl or (NR A R B )carbonyl;
  • R 9 is selected from hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, carboxy, carboxyalkyl, cyano, cyanoalkyl, formyl, halogen, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, nitro, - NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl or (NR A R B )sulfonyl;
  • X is selected from CH, CR X or N;
  • Y is selected from CH, CR Y or N;
  • Z is selected from CH, CRz or N;
  • Rx, Ry and Rz are each independently selected from alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylcarbony
  • L, A, D, Ri, R 2 , R 3 , R A , and R B are as defined in formula (I).
  • compounds of the present invention have formula (VII) wherein A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle; P, Q, D, L, R A , R B , and R 3 , are as defined in formula (I) and R 4 , R ⁇ , R 7 , Rg, and R 9 are defined as in formula (VII).
  • compounds of the present invention have formula (VII) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2-methyl-l -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1- dioxidothiomo ⁇ holinyl; R 8 is cyano; and P, Q, D, L, R A , R B , and R 3 , are as defined in formula (I) and j, Re, R 7 , and R9 are defined as in formula (VII).
  • compounds of the present invention have formula (VII) wherein A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)-3- (dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)-3- hydroxy-1 -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2-(hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6-dimethylpiperidinyl, 4-methyl- 1 -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)-2,5-dimethylpyrrolidinyl, (cis)-2,
  • compounds of the present invention have formula (VII) wherein L is -CH 2 CH 2 -; A is a covalent bond; Ri and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from azepanyl, azetidinyl, imadazolyl, mo ⁇ holinyl, piperazinyl, piperidinyl, pyridinyl, pyrrolidinyl, (2R)-2- methyl-1 -pyrrolidinyl, 2,5-dihydro-lH-pyrrolyl, pyrrolyl, 3,6-dihydro-l(2H)-pyridinyl, thiomo ⁇ holinyl, and 1,1 -dioxidothiomo ⁇ holinyl; R 3 , R 4 , R ⁇ , R7 and R 9 are hydrogen; Rg is cyano; X is CH;Y is CH; and Z is CH.
  • compounds of the present invention have formula (VII) wherein L is -CH 2 CH 2 -; A is a covalent bond; R ⁇ and R 2 taken together with the nitrogen atom to which they are attached, together form a heterocycle selected from 1 -azepanyl, (3S)- 3-(dimethylamino)pyrrolidinyl, (3R)-3-(dimethylamino)pyrrolidinyl, lH-imidazol-1-yl, (3R)- 3-hydroxy-l -pyrrolidinyl, (3 S)-3 -hydroxy- 1 -pyrrolidinyl, (2S)-2- (hydroxymethyl)pyrrolidinyl, (2R)-2-(hydroxymethyl)pyrrolidinyl, (cis)-2,6- dimethylpiperidinyl, 4-methyl-l -piperidinyl, 2-methyl-l -piperidinyl, 1 -piperidinyl, (2R,5R)- 2,5-dimethylpyr
  • the present invention also provides, pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula (I- VII) in combination with a pharmaceutically acceptable carrier.
  • the present invention provides a method of selectively modulating the effects of the histamine-3 receptors in a mammal comprising administering an effective amount of a compound of formula (I- VII).
  • the present invention provides a method of treating or preventing a disorder ameliorated by modulating the histamine-3 receptors in a mammal comprising administering an effective amount of a compound of formula (I -VII).
  • the present invention provides a method of treating a disorder selected from acute myocardial infarction, asthma, bipolar disorder, cognitive enhancement, cognitive deficits in psychiatric disorders, cutaneous carcinoma, drug abuse, depression, gastrointestinal disorders, inflammation, jet lag, medullary thyroid carcinoma, melanoma, allergic rhinitis, Meniere's disease, migraine, mood and attention alteration, motion sickness, neurogenic inflammation, obsessive compulsive disorder, pain, Parkinson's disease, schizophrenia, seizures, septic shock, Tourette's syndrome, vertigo, or wakefulness.
  • a disorder selected from acute myocardial infarction, asthma, bipolar disorder, cognitive enhancement, cognitive deficits in psychiatric disorders, cutaneous carcinoma, drug abuse, depression, gastrointestinal disorders, inflammation, jet lag, medullary thyroid carcinoma, melanoma, allergic rhinitis, Meniere's disease, migraine, mood and attention alteration, motion sickness, neurogenic inflammation, obsessive compulsive disorder, pain, Parkinson
  • the present invention provides a method of treating Alzheimer's disease by administering an effective amount of a compound of formula (I-VII).
  • the present invention provides a method of treating attention-deficit hyperactivity disorder by administering an effective amount of a compound of formula (I- VII).
  • the present invention provides a method of treating epilepsy by administering an effective amount of a compound of formula (I- VII).
  • the present invention provides a method of treating narcolepsy by administering an effective amount of a compound of formula (I- VII).
  • the present invention provides a method of treating obesity by administering an effective amount of a compound of formula (I- VII).
  • the present invention provides a method of treating a disorder selected from mild cognitive impairment, deficits of memory, and deficits of learning and dementia by administering an effective amount of a compound of formula (I- VII).
  • Representative compounds of the invention include, but are not limited to: 2R)-2-methylpyrrolidinyl]ethyl ⁇ - 1 -benzofuran-5-yl)benzonitrile; -pyrrolidinyl)ethyl]- 1 -benzofuran-5-yl ⁇ benzonitrile; -methyl- 1 -pyrrolidinyl)ethyl]- 1 -benzofuran-5-yl ⁇ benzonitrile; -piperidinyl)ethyl]- 1 -benzofuran-5-yl ⁇ benzonitrile; iethylamino)ethyl]-l-benzofuran-5-yl ⁇ benzonitrile; -methyl- 1 -piperidinyl)ethyl]- 1 -benzofuran-5-yl ⁇ benzonitrile; 3R)-3-hydroxypy ⁇ Olidinyl]ethyl ⁇ -l-benzofuran-5-yl)benz
  • H 3 receptor ligands histamine-3 receptor ligands
  • Sprague-Dawley rat brain cortices were homogenized (1 g tissue/10 mL buffer) in 50 mM Tris-HCl/5 mM EDTA containing protease inhibitor cocktail (Calbiochem) using a polytron set at 20,500 ⁇ m. Homogenates were centrifuged for 20 minutes at 40,000 ⁇ g. The supernatant was decanted, and pellets were weighed. The pellet was resuspended by polytron homogenization in 40 mL 50 mM Tris-HCl/5 mM EDTA with protease inhibitors and centrifuged for 20 minutes at 40,000xg.
  • the membrane pellet was resuspended in 6.25 volumes (per gram wet weight of pellet) of 50 mM Tris-HCl/5 mM EDTA with protease inhibitors and aliquots flash frozen in liquid N 2 and stored at -70 °C until used in assays.
  • Rat cortical membranes (12 mg wet weight/tube) were incubated with ( 3 H)-N- ⁇ -methylhistamine (-0.6 nM) with or without H 3 receptor antagonists in a total incubation volume of 0.5 mL of 50 mM Tris-HCl/5 mM EDTA (pH 1.1).
  • Test compounds were dissolved in DMSO to provide a 20 mM solution, serially diluted and then added to the incubation mixtures prior to initiating the incubation assay by addition of the membranes. Thioperamide (3 ⁇ M) was used to determine nonspecific binding. Binding incubations were conducted for 30 minutes at 25 °C and terminated by addition of 2 mL of ice cold 50 mM Tris-HCl (pH 1.1) and filtration through 0.3% polyethylenimine-soaked Unifilter plates (Packard). These filters were washed 4 additional times with 2 mL of ice-cold 50 mM Tris- HCl and dried for 1 hour. Radioactivity was determined using liquid scintillation counting techniques. Results were analyzed by Hill transformation and Ki values were determined using the Cheng-Prusoff equation.
  • the compounds of the present invention bind to the histamine-3 receptors and therefore may have utility in the treatment of diseases or conditions ameliorated with histamine-3 receptor ligands.
  • Compounds of the present invention are histamine-3 receptor ligands that modulate function of the histamine-3 receptor by antagonizing the activity of the receptor. These compounds may be inverse agonists that inhibit the basal activity of the receptor or they may be antagonists that completely block the action of receptor-activating agonists. These compounds may also be partial agonists that partially block or partially activate the histamine-3 receptor receptor or they may be agonists that activate the receptor.
  • the compounds of this invention can be prepared by a variety of synthetic procedures.
  • Benzofurans of general formula (5) wherein L, Ri, R 2 , R 3 , R t , R 5 , Re and R are as defined in formula (I), may be prepared as described in Scheme I.
  • Phenols of general formula (1) may be treated with sodium hypochlorite, sodium iodide and sodium hydroxide in a solvent such as methanol to provide iodides of general formula (2).
  • Iodides of general formula (2) may be treated with substituted propargyl alcohols, dichlorobis(triphenylphosphine)palladium, copper iodide, a base such as triethylamine in a solvent such as DMF with heat to provide benzofurans of general formula (3).
  • Alcohols of general formula (3) may be treated with methanesulfonyl chloride or methanesulfonyl anhydride, a base such as triethylamine, diisopropylethylamine or N-methylmo ⁇ holine in a solvent such as dichloromethane or THF to provide mesylates of general formula (4).
  • Mesylates of general formula (4) may be treated with secondary or primary amines in solvents such as DMF or THF with heat to provide amines of general formula (5).
  • mesylates of general formula (4) may be treated with secondary or primary amine hydrochlorides in the presence of a base such as triethylamine, diisopropylethylamime or N-methylmo ⁇ holine in a solvent such as DMF or THF with heat to provide benzofurans of general formula (5).
  • a base such as triethylamine, diisopropylethylamime or N-methylmo ⁇ holine in a solvent such as DMF or THF with heat to provide benzofurans of general formula (5).
  • Benzofurans of general formula (10), wherein L, Ri, R 2 , R 3 , R-i, R 5 , R 7 , Rg, R , X, Y and Z are as defined in formula (II), may be prepared as described in Scheme 2.
  • Halides of general formula (6) may be treated with boronic acids of general formula (7), under Suzuki conditions such as tetrakis(triphenylphosphine)palladium, a base such as aqueous sodium carbonate in a solvent such as toluene with heat to provide tert-butyldimethylsilyl protected alcohols of general formula (8).
  • Protected alcohols of general formula (8) may be treated with tetrabutylammonium fluoride in a solvent such as THF to provide phenols of general formula (9).
  • Phenols of general formula (9) may be treated using conditions as described in Scheme 1 to provide benzofurans of general formula (10).
  • Benzofurans of general formula (12) wherein L, Ri, R 2 , R 3 , R , R 5 , Re, X, Y, Z, Rg, and R 9 are as defined in formula (III), may be prepared as described in Scheme 3.
  • Boronic acids of general formula (11) may be treated with halides as described in Scheme 2 to provide compounds of general formula (11a).
  • Compounds of general formula (11a) may be treated with tetra-butylammonium fluoride and then as described in Scheme 1 and Scheme 2 to provide benzofurans of general formula (12).
  • Chromenes of general formula (19), wherein L, Ri, R 2 , R 3 , Rt, R 5 , R 7 , R 8 , R 9 , X, Y and Z are as defined by formula (II), may be prepared as described in Scheme 4.
  • Boronic acids of general formula (13) may be treated with halides of general formula (6), tetrakis(triphenylphosphine)palladium, a base such as aqueous sodium carbonate in a solvent such as toluene with heat to provide compounds of general formula (14).
  • Compounds of general formula (14) may be treated with n-butyl lithium, N, N, N', N'- tetramethylethylenediamine followed by DMF or acetyl chloride to provide compounds of general formula (15) which may be treated with [2-(dimethylamino)-2-oxoethyl]lithium in a solvent such as THF to provide compounds of general formula (16).
  • Compounds of general formula (16) may be treated with acetic acid with heat to provide chromenes of general formula (17).
  • Chromenes of general formula (17) may be treated with butyl lithium, N, N, N', N'-tetramethylethylenediamine followed by ethylene oxide or trimethylene oxide to provide alcohols of general formula (18).
  • Alternatively (17) may be treated with butyl lithium, N, N, N', N'-tetrarnethylethylenediamine and (2-bromoethoxy) tert- butyldimethylsilane followed by tetrabutylammonium fluoride deprotection to provide alcohols of general formula (18).
  • Alcohols of general formula (18) may be converted to the respective mesylate and further reacted with amines as described in scheme 1 to provide chromenes of general formula (19).
  • chromenes of general formula (24) wherein L, R ls R 2 , R 3 , R 4 , R 5 , R 7 , R 8 and R are as defined in formula (II), may be prepared as described in scheme 5.
  • Compound of general structure (21) may be prepared from Scheme 4 by substituting compound of general structure (20) for compound of general formula (14).
  • Compound of general formula (20) may be treated with n-butyl lithium followed by DMF or acetyl chloride to provide compounds of general formula (20a).
  • Compounds of general formula (20a) may be treated with [2-(dimethylamino)-2-oxoethyl]lifhium followed by acetic acid and heat to provide chromenes of general formula (21).
  • Chromenes of general formula (21) may be treated with n-butyl lithium, N, N, N', N'-tetramethylethylenediamine followed by ethylene oxide or trimethylene oxide to provide alcohols which may be treated with methanesulfonyl chloride, a base such as triethylamine, diisopropylethylamine or N-methylmo ⁇ holine in a solvent such as dichloromethane or THF to provide mesylates which may be treated with secondary or primary amines in solvents such as DMF or THF with heat to provide amines of general formula (22).
  • Amines of general formula (22) may be treated with tetrabutylammonium fluoride followed by treatment with triflic anhydride, pyridine and boronic acids of general formula (23), dichlorobis(triphenylphosphine)palladium, cesium carbonate in a solvent such as DMF with heat to provide compound of general formula (24).
  • chromenes of general structure (28), wherein Ri, R 2 , R 3 , R 4 , R 5 , R ⁇ and R 7 are as defined by formula (III), may be prepared as described in Scheme 6.
  • Phenols of general formula (25) may be treated with compounds of general formula (26) and hydrobromic acid in acetic acid with heat to provide compounds of general formula (27), which may be treated with amines as described in Scheme 4 to provide chromenes of general formula (28).
  • Chromenes of general formula (30) wherein L, Ri, R2, R3, R4, R5, R-, Rs, R9, X, Y and Z are as defined in formula (III), may be prepared as described in Scheme 7.
  • Boronic acids of general formula (29) may be treated as described in Scheme 4 to provide Chromenes of general formula (30).
  • Alcohols of general formula (34) may be treated with methanesulfonyl chloride with bases such as triethylamine, diisopropylethylamine or N-methylmo ⁇ holine in solvents such as dichloromethane or THF to provide mesylates of general formula (35).
  • Mesylates of general formula (35) may be treated with secondary or primary amines in a solvent such as DMF or THF with heat to provide amines of general formula (36).
  • Dihydrofurans of general formula (38) wherein Ri, R 2 , R3, i, R5, Re, R_, R 9 , X, Y and Z are as defined in formula (IV), may be prepared as described in Scheme 9.
  • Iodides of general formula (37) may be treated as described in Scheme 8 to provide dihydrofurans of general formula (38).
  • Benzothiophenes of general formula (43) wherein L, R ⁇ , R2, R 3 , R», R 5 , R 7 , R 8 , R 9 , X, Y and Z are defined in formula (I), may be prepared as described in Scheme 10.
  • Compounds of general formula (39) may be treated with poly-phosphoric acid with heat to provide benzothiophenes of general formula (40).
  • Benzothiophenes of general formula (40) may be treated with boronic acids, tetrakis(triphenylphosphine)palladium, a base such as aqueous sodium carbonate in a solvent such as toluene with heat to provide compounds of general formula (41).
  • Compounds of general formula (41) may be treated with n-butyl lithium, N, N, N', N'-tetramethylethylenediamine followed by ethylene oxide to provide alcohols of general formula (42).
  • Alcohols of general formula (42) may be converted to the mesylate and then further treated with amines as described in Scheme 1 to provide benzothiophenes of general formula (43).
  • Benzothiophenes of general formula (45) wherein Ri, R 2 , R 3 , R 4 , R 5 , Re, Rg, R 9 and X, Y and Z are defined in formula (I), may be prepared as described in Scheme 1 1.
  • Compounds of general formula (44) may be processed as described in Scheme 10 to provide compounds of general formula (45).
  • Benzofurans of general formula (49) wherein R ⁇ , R 2 , R 3 , R , R 5 , Re, and R are as defined in formula (I), may be prepared as described in Scheme 12.
  • Alkynes of general formula (48) may be treated with a phenol of general formula (2), a palladium catalyst such as palladium(II) acetate, a triarylphoshine such as triphenylphoshine or tris(2-mefhylphenyl)phosphine, copper iodide, and a base such as diisopropylamine in a solvent such as acetonitrile followed by heat to provide benzofurans of general formula (49).
  • a palladium catalyst such as palladium(II) acetate
  • a triarylphoshine such as triphenylphoshine or tris(2-mefhylphenyl)phosphine
  • copper iodide copper iodide
  • a base such as diisopropylamine in a solvent such as acetonitrile followed by heat to provide benzofurans of general formula (49).
  • Example 1A 4'-hvdroxy-3'-iodor 1 , 1 '-biphenyl1-4-carbonitrile
  • 4-hydroxy-4'-cyanobiphenyl 6.00 g, 30.8 mmol
  • sodium iodide 4.61 g, 30.8 mmol
  • sodium hydroxide 1.23 g, 30.8 mmol
  • methanol 90 mL
  • an aqueous solution of sodium hypochlorite 47 mL of 5.25% CloroxTM, 2.29 g, 30.8 mmol
  • Example IB 4-[2-(2-hvdroxyethylH-benzofuran-5-yl]benzonitrile
  • a solution of Example 1A (5.19 g, 16.2 mmol), triethylamine (5.60 mL, 40.4 mmol) and 3-butyn-l-ol (1.90 g, 27.2 mmol) in dimethylformamide (13 mL) at 20 °C was added cuprous iodide (0.46 g, 2.4 mmol) and bis-triphenylphosphine palladium dichloride (0.56 g, 0.80 mmol).
  • dichloromethane 10 mL
  • methane sulfonyl chloride 0.79 g, 4.5 mmol
  • the mixture was stirred for 30 min., diluted with dichloromethane, washed with water, dried (Na2SO 4 ), filtered and concentrated under reduced pressure. The residue was chromatographed on silica with dichloromethane to give the titled compound (0.66 g, 89%).
  • 2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl) - 1 -benzofuran-5-yl benzonitrile A suspension of Example IC (0.19 g, 0.55 mmol), (2R)-2-methylpyrrolidine hydrobromide (0.17 g, 1.0 mmol) and sodium carbonate (0.23 g, 2.2 mmol) in acetonitrile (0.4 mL) was heated to 50 °C with stirring for 48 hours. The reaction was cooled to ambient temperature, diluted with acetonitrile and centrifuged. The supernatant liquid was removed and the solids washed with acetonitrile.
  • Example 2 4- ⁇ 2-r2-(l -pyrrolidinyDethyl]- 1 -benzofuran-5-yl ⁇ benzonitrile
  • the product from Example IC and pyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 3 4- ⁇ 2-[2-(2-methyl-l-pyrrolidinyl)ethyl]-l-benzofuran-5-yl ⁇ benzonitrile
  • the product from Example 1 C and 2-methyl-pyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 4 4-(2-[2-(l-piperidinyl)ethyll-l-benzofuran-5-yl ⁇ benzonitrile
  • the product from Example IC and piperidine were processed as described in Example ID to provide the titled compound.
  • ⁇ NMR (300 MHz, CD 3 OD) ⁇ 7.88 (m, IH), 7.80 (m, 4H), 7.60 (m, 2H), 6.82 (s, IH), 3.65 (m, 2H), 3.55 (m, 2H), 3.33 (m, 2H), 3.05 (m, 2H), 2.0 (m, 2H), 1.5-1.9 (m, 4H);
  • Example 5 4-(2- 2-(diethylamino)ethvn-l-benzofuran-5-v benzonitrile
  • the product from Example 1 C and diethylamine were processed as described in Example ID to provide the titled compound.
  • Example 6 4-(2-[2-(2-methyl-l-piperidinyl)ethyll-l-benzofuran-5-yl ⁇ benzonitrile
  • the product from Example IC and 2-methylpiperidine were processed as described in Example ID to provide the titled compound.
  • Example 7 4-(2- ⁇ 2-[( ' 3R)-3-hvdroxypyrrolidinyl1ethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and 3-(R)-hydroxypyrrolidine were processed as described in Example ID to provide the titled compound.
  • ⁇ NMR (300 MHz, CD 3 OD) ⁇ 7.88 (m, IH), 7.80 (m, 4H), 7.60 (m, 2H), 6.80 (s, IH), 4.55 (bs, IH), 3.8-3.9 (m, 4H), 3.25-3.5 (m, 4H), 2.05-2.4 (m, 2H); MS (DCI) m/z 333 (M+H) + .
  • Example 8 4- ⁇ 2- 2-(lH-imidazol-l-yl)ethyl]-l-benzofuran-5-yllbenzonitrile
  • the product from Example IC and imidazole were processed as described in Example ID to provide the titled compound.
  • Example 9 4-(2-(2-[(3S)-3-(dimethylamino)pyrrolidinyl]ethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and 3-(S)-(dimethylamino)pyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 10 4-(2- ⁇ 2-r(2S)-2-(hvdroxymethyl)pyrrolidinyl1ethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example 1 C and 2-(S)-(hydroxymethyl)pyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 11 4-(2- ⁇ 2- -2,6-dimethylpiperidinyl]ethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and -dimethylpiperidine were processed as described in Example ID to provide the titled compound.
  • Example 12 4-(2- ⁇ 2-r(2R.5R)-2.5-dimethylpyrrolidinyl1ethvU-l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and (2R,5R)-dimethylpyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 13 4- (2-[2-f 1 -azepanvDethyl]- 1 -benzofuran-5 -yl ⁇ benzonitrile
  • the product from Example IC and azepine were processed as described in Example ID to provide the titled compound.
  • Example 14 4-
  • the product from Example IC and 4-methylpiperidine were processed as described in Example ID to provide the titled compound.
  • Example 15 4-(2-(2-r2-pyrrolidine methyl carboxylatelethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and (L)-proline methyl ester were processed as described in Example ID to provide the titled compound.
  • Example 16 4-(2- 2-(3.6-dihvdro-l(2H)-pyridinyl)ethyl]-l-benzofuran-5-yl ⁇ benzonitrile
  • the product from Example IC and 1,2,3,6-tetrahydropyridine were processed as described in Example ID to provide the titled compound.
  • Example 17 4-(2- ⁇ 2-f(2R)-2-(hvdroxymethyl)pyrrolidinyl1ethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and (D)-prolinol were processed as described in Example ID to provide the titled compound.
  • ⁇ NMR (300 MHz, CD 3 OD) ⁇ 7.87 (m, IH), 7.82 (m, 4H), 7.58 (m, 2H), 6.80 (s, IH), 3.95 (m, 2H), 3.72 (m, 2H), 3.58 (m, IH), 3.35-3.4 (m, 4H), 1.95-2.3 (m, 4H); MS (DCI) m/z 347 (M+H) + .
  • Example 18 4-(2-f2-rtert-butyl(methyl aminolethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and tert-butyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 19 4-(2- ⁇ 2-[isopropyl(methyl)aminolethyl. -l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and isopropyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 20 4-(2- ⁇ 2- isobutyl(methyl)amino]ethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example 1 C and isobutyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 21 4-(2-(2-rethyl(isopropyl)amino]ethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the product from Example IC and ethyl(isopropyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 22 4-(2- j2-rethyl(propyl)amino]ethvU - 1 -benzofuran-5-yl)benzonitrile
  • the product from Example IC and ethyl (propyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 23A 4'-(4-mo ⁇ holinylcarbonyl)[l. -biphenyl]-4-ol
  • 4-hydroxy-biphenyl-4'-carboxylic acid 5.35 g, 25.0 mmol
  • mo ⁇ holine 2.39 g, 27.5 mmol
  • triethylamine 3.5 mL, 25 mmol
  • dichloromethane 100 mL
  • l-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was stirred for 16 hours, diluted with aqueous NaH 2 PO 4 and filtered.
  • Example 23B 3-iodo-4'-(4-mo ⁇ holinylcarbonyl)r 1.1 '-biphenyll-4-ol
  • Example 23 C 2- ⁇ 5- 4-(4-mo ⁇ holinylcarbonyl)phenyl]-l-benzofuran-2-yl ⁇ ethanol
  • MS (DCI) m/z 352 (M+H) + .
  • Example 23 D 2-
  • the product from Example 23C was processed as described in Example IC to provide the titled compound.
  • Example 23E 4-(4- ⁇ 2- 2-(2-methyl-l-pyrrolidinyl)ethyll-l-benzofuran-5-yl ⁇ benzoyl)mo ⁇ holine
  • the product from Example 23 D and 2-methyl-pyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 24 4-(4- ⁇ 2- 2-(l-piperidinyl)ethyl]-l-benzofuran-5-yl ⁇ benzoyl)mo ⁇ holine
  • the product from Example 23 D and piperidine were processed as described in Example ID to provide the titled compound.
  • Example 25 N.N-diethyl-N-(2- ( 5 -f 4-(4-morpholinylcarbonyl)phenv ⁇ - 1 -benzofuran-2-yl ⁇ ethyllamine
  • the product from Example 23D and diethylamine were processed as described in Example ID to provide the titled compound.
  • Example 26 4-(4- ⁇ 2- 2-(2-methyl- 1 -piperidinvDethyl]- 1 -benzofuran-5-yl ⁇ benzoyl)mo ⁇ holine
  • the product from Example 23D and 2-methyl-piperidine were processed as described in Example ID to provide the titled compound.
  • Example 27 (3R)-l-(2-
  • the product from Example 23D and 3-(R)-pyrrolidinol were processed as described in Example ID to provide the titled compound.
  • Example 29 4-[4-(2- ⁇ 2-[-2.6-dimethylpiperidinyl]ethyl ⁇ -l-benzofuran-5-yl)benzoyllmorpholine
  • the product from Example 23D and -dimethylpiperidine were processed as described in Example ID to provide the titled compound.
  • Example 30 4-(4- ⁇ 2- 2-(azepanyl)ethyll-l-benzofuran-5-yl ⁇ benzoyl)mo ⁇ holine
  • the product from Example 23D and azepane were processed as described in Example ID to provide the titled compound.
  • Example 31 4-(4- .2-r2-(4-methyl- 1 -piperidinvDethyll- 1 -benzofuran-5-yl ⁇ benzoyl)mo ⁇ holine
  • the product from Example 23D and 4-methyl piperidine were processed as described in Example ID to provide the titled compound.
  • Example 32 4-(4-(2-r2-(4-mo ⁇ holine)ethyl]-l-benzofuran-5-yl ⁇ benzoyl ' )mo ⁇ holine
  • the product from Example 23D and mo ⁇ holine were processed as described in Example ID to provide the titled compound.
  • Example 33 4-(4-(2-r2-(3,6-dihvdro-l(2H)-pyridinyl ethyl]-l-benzofuran-5-yl ⁇ benzoyl)mo ⁇ holine
  • the product from Example 23D and 1,2,3,6-tetrahydropyridine were processed as described in Example ID to provide the titled compound.
  • Example 34 4-(4- ⁇ 2- 2-(2S)-pyrrolidinylmethano ⁇ ethvn-l-benzofuran-5-yl ⁇ benzoyl mo ⁇ holine
  • the product from Example 23D and 2-(S)-(hydroxymethyl)pyrrolidine were processed as described in Example ID to provide the titled compound.
  • ⁇ NMR (300 MHz, CD 3 OD) 8 7.81 (m, IH), 7.73 (m, 2H), 7.55 (m, 2H), 7.50 (dm 2H, J 8.4Hz), 6.77 (s, IH), 3.3-4.0 (m, 17H), 1.9-2.3 (m, 4H); MS (DCI) m/z 434 (M+H) + .
  • Example 35 N-(tert-butyl)-N-methyl-N-(2- ⁇ 5-
  • the product from Example 23 D and tert-butyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 36 N-isopropyl-N-methyl-N-(2- ⁇ 5- 4-(4-mo ⁇ holinylcarbonyl)phenyl]- 1 -benzofuran-2- yllethvDamine
  • the product from Example 23D and isopropyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 37 N-isobutyl-N-methyl-N-(2-(5-[4-(4-mo ⁇ holinylcarbonyl)phenyl1-l-benzofuran-2- vUethvDamine
  • the product from Example 23 D and isobutyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 38 N-ethyl-N-isopropyl-N-(2- ⁇ 5- 4-(4-mo ⁇ holinylcarbonyl)phenyll-l-benzofuran-2- yl ⁇ ethvDamine
  • the product from Example 23D and isopropyl(ethyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 39 N,N-dimethyl-N-(2- ⁇ 5-[4-(4-mo ⁇ holinylcarbonyl)phenyll- 1 -benzofuran-2-yl ⁇ ethvDamine
  • Example 40 N-ethyl-N-(2- ⁇ 5- 4-(4-mo ⁇ holinylcarbonvDphenyl]- 1 -benzofuran-2-yl ⁇ ethvD-N- propylamine
  • the product from Example 23D and ethyl(propyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 41 A 3-(2-bromoethyD-6-hydroxy-4-methyl-2H-chromen-2-one To a solution of resorcinol (7.03 g, 64.0 mmol) in a solution consisting of HBr (104 mL, 422 mmol) and glacial acetic acid (10 mL) at 0 °C was slowly added 2-acetylbutyrolactone (5.8 mL, 54 mmol). The mixture was warmed to ambient temperature and then heated to reflux for 2 hours. The mixture was cooled to ambient temperature and diluted with water (350 mL). The mixture was filtered and the solid dried in vacuo overnight to give the titled compound (15.5 g, 85%).
  • Example 41B 6-hydroxy-4-methyl-3-[ " 2-(l-pyrrolidinyDethyl]-2H-chromen-2-one
  • a solution of Example 41 A (0.20 g, 0.70 mmol) and pyrrolidine (0.50 mL, 6.0 mmol) in DMF (2 mL) was heated to 75 °C for 16 hours, cooled to ambient temperature, diluted with water (20 mL) and extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate was dried (MgS0 4 ), filtered, concentrated under reduced pressure and chromatographed on silica with 10 % methanol in dichloromethane to give the titled compound (0.48 g, 25%).
  • Example 41C To a solution of Example 41B (0.105 g, 0.38 mmol), N-phenyltrifluoromethane sulfonimide (0.143 g, 0.38 mmol) in dichloromethane (2 mL) at 0 °C was added triethylamine (0.68 mL, 0.48 mmol). The mixture was stirred at ambient temperature for 12 hours, diluted with diethyl ether (40 mL) and washed sequentially with aqueous NaOH (IN, 2 x 30 mL), water and brine, dried (MgS0 ), filtered and evaporated to provide the triflate.
  • Example 42 4- ⁇ 4-methyl-2-oxo-3-r2-(l-piperidinvDethyl]-2H-chromen-6-yl ⁇ benzonitrile
  • the product from Example 41 A and piperidine were processed as described in Examples 41B and 41C to provide the titled compound.
  • Example 43 4- ⁇ 3-[2-(diethylamino)ethyl1-4-methyl-2-oxo-2H-chromen-6-yl ⁇ benzonitrile
  • the product from Example 41 A and diethylamine were processed as described in Examples 41B and 41C to provide the titled compound.
  • Example 44A 4-[(6-chloro-3-pyridinvDcarbonyllmo ⁇ holine To a solution of chloronicotinoyl chloride (3.52 g, 2.00 mmol) and triethylamine (3.1 mL, 2.22 mmol) in dichloromethane (5 mL) at 0 °C was slowly added mo ⁇ holine (1.75 mL, 2.00 mmol). The mixture was warmed to ambient temperature, washed with water (2 x 25 mL), brine (1 x 25 mL), dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure. The product was chromatographed on silica with ethyl acetate to give the titled compound (4.0 g, 88%). MS (DCI) m/z 227 (M+H) + .
  • Example 44B 4-f 5-(4-mo ⁇ holinylcarbonyD- 1 ,6-dihvdro-2-pyridinyl1phenol
  • Example 44C 2-iodo-4- 5-(4-mo ⁇ holinylcarbonvD-2-pyridinyl]phenol
  • a mixture of Example 44B (4.25 g, 15.0 mmol) sodium iodide (2.36 g, 15.7 mmol) and sodium hydroxide (0.63 g, 15.7 mmol) was stirred in methanol (90 mL) with heating until a clear solution was obtained. The solution was then cooled to 0 °C and to this was slowly added sodium hypochlorite (22 mL of 5.25%, 1.15 g, 15.5 mmol) (CloroxTM) over 45 minutes.
  • sodium hypochlorite 22 mL of 5.25%, 1.15 g, 15.5 mmol
  • Example 44D 2- ⁇ 5-[5-(4-mo ⁇ holinylcarbonyD-2-pyridinyl]-l -benzofuran-2 -vPethanol
  • a solution of Example 44C (2.85 g, 6.95 mmol), triethylamine (2.4 mL, 17.4 mmol), and 3-butyn-l-ol (0.73 g, 10.4 mmol) in dimethylformamide (15 mL) at 20 °C was added cuprous iodide (0.2 g, 1.0 mmol) and bis-triphenylphosphine palladium dichloride (0.24 g, 0.35 mmol). The mixture was stirred for one hour, then heated to 65 °C for 16 hours.
  • Example 44E 2- .5-[5-(4-mo ⁇ holinylcarbonvD-2-pyridinyl]- 1 -benzofuran-2-yl ⁇ ethyl methanesulfonate
  • the product from Example 44D was processed as described in Example IC to provide the titled compound.
  • Example 44F 4-[(6- ⁇ 2- 2-(l-pyrrolidinvDethyl]-l-benzofuran-5-yl ⁇ -3-pyridinvDcarbonyl]mo ⁇ holine
  • the product from Example 44E and pyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 44E The product from Example 44E and 2-(R)-methylpyrrolidine were processed as described in Example ID to provide the titled compound. MS (DCI) m/z 420 (M+H) + .
  • Example 46 4-[(6- ⁇ 2-f2-( 1 -piperidinvDethyll- 1 -benzofuran-5-yl) -3-pyridinvDcarbonyl]mo ⁇ holine
  • the product from Example 44E and piperidine were processed as described in Example ID to provide the titled compound.
  • Example 47 4-[(6-(2-r2-(N,N-diethvDethyl]-l-benzofuran-5-yl ⁇ -3-pyridinvDcarbonyl1mo ⁇ holine
  • the product from Example 44E and diethylamine were processed as described in Example ID to provide the titled compound.
  • Example 48 (3R)-l-r2-(5-f5-( ' 4-morpholinylcarbonyl)-2-pyridinyl1-l-benzofuran-2-yllethvD-3- pyrrolidinol
  • the product from Example 44E and 3-(R)-hydroxypyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 49 4-(r6-(2-(2-[(2R.5R)-2.5-dimethylpyrrolidinyl]ethvD-l-benzofuran-5-vD-3- pyridinyl]carbonyl ⁇ mo ⁇ holine
  • the product from Example 44E and (2R,5R)-dimethylpyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 50 4-(r6-(2-(2-[-2,6-dimethylpiperidinyl1ethvU-l-benzofuran-5-vD-3- pyridinyl]carbonyl ⁇ mo ⁇ holine
  • the product from Example 44E and -dimethylpiperidine were processed as described in Example ID to provide the titled compound.
  • Example 51 4-([6-r2-(2-[l-azepanyl]ethyl)-l-benzofuran-5-yD-3-pyridinyl]carbonyllmorpholine
  • the product from Example 44E and azepine were processed as described in Example ID to provide the titled compound.
  • Example 52 4-r.6-l2-r2-(4-methyl-l-piperidinvDethyl]-l-benzofuran-5-vU-3- pyridinvDcarbonyllmo ⁇ holine
  • the product from Example 44E and 4-methylpiperidine were processed as described in Example ID to provide the titled compound.
  • Example 53 4-[(6-(2-r2-(4-mo ⁇ holinyl)ethyl1-l-benzofuran-5-vU-3-pyridinyl)carbonyl1mo ⁇ holine
  • the product from Example 44E and mo ⁇ holine were processed as described in Example ID to provide the titled compound.
  • Example 54 N-(tert-butvD-N-methyl-N-(2- ⁇ 5-[5-(4-m ⁇ holinylcarbonvD-2 -pyridinyl]-! -benzofuran-2- yl. ethvDamine
  • the product from Example 44E and tert-butyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 55 N-isobutyl-N-methyl-N-(2- (5-[5-(4-mo ⁇ holinylcarbonvD-2-pyridinyl]- 1 -benzofuran-2 - yl) ethvDamine
  • the product from Example 44E and isob ⁇ tyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 56 N-isopropyl-N-methyl-N-(2-(5-r5-(4-mo ⁇ holinylcarbonyl)-2-pyridinyll-l-benzofuran-2- yl ⁇ ethvDamine
  • the product from Example 44E and isopropyl(methyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 57 N-ethyl-N-isopropyl-N-(2- ⁇ 5-r5-(4-mo ⁇ holinylcarbonyD-2 -pyridinyl]- 1-benzo furan-2- yl ⁇ ethvDamine
  • the product from Example 44E and ethyl(isopropyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 58 N.N-dimethyl-N-(2- ⁇ 5-[5-(4-mo ⁇ holinylcarbonyD-2 -pyridinyl]- l-benzofuran-2- yl) ethvDamine
  • the product from Example 44E and dimethylamine were processed as described in Example ID to provide the titled compound.
  • Example 59 N-ethyl-N-propyl-N-(2- (5-r5-(4-mo ⁇ holinylcarbonvD-2-pyridinyl1- 1 -benzofuran-2 - yll ethvDamine
  • the product from Example 44E and ethyl(propyl)amine were processed as described in Example ID to provide the titled compound.
  • Example 60 8-(2- ⁇ 5-f5-(4-mo ⁇ holinylcarbonyl)-2-pyridinyl1-l-benzofuran-2-vUethvD-l,4-dioxa-8- azaspiro[4.5]decane
  • the product from Example 44E and l,4-dioxa-8-azaspiro[4.5]decane were processed as described in Example ID to provide the titled compound.
  • Example 61 5-(2-(5-[5-(4-mo ⁇ holinylcarbonyD-2-pyridinyl1-l -benzofuran-2-yl ⁇ ethvD-2-oxa-5- azabicyclo[2.2. l]heptane
  • the product from Example 44E and 2-oxo-5-azabicyclo[2.2.1]heptane were processed as described in Example ID to provide the titled compound.
  • Example 62 (2S)-l-(2- ⁇ 5-[5-(4-mo ⁇ holinylcarbonyD-2-pyridinyl1-l-benzofuran-2-yl ⁇ ethvD-2- pyrrolidinol
  • the product from Example 44E and 2-(R)-hydroxymethylpyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 63 N-allyl-N-(2-(5-[5-C4-morpholinylcarbonvD-2-pyridinvn-l-benzofuran-2-yllethvDamine
  • the product from Example 44E and allylamine were processed as described in Example ID to provide the titled compound.
  • ⁇ NMR 300 MHz, CD 3 OD
  • ⁇ 8.70 m, IH
  • 7.96 m, 3H
  • 7.59 7.59
  • J 8.7 Hz, IH
  • 6.81 s, IH
  • 5.95 m, IH
  • 5.55 m, 2H
  • MS (DCI) m/z 392 (M+H) + MS (DCI) m/z 392 (M+H) + .
  • Example 64 3-[(2-(5-[5-(4-mo ⁇ holinylcarbonvD-2-pyridinvn-l-benzofuran-2-yl ⁇ ethvDamino]-l- propanol
  • the product from Example 44E and 3-amino-l-propanol were processed as described in Example ID to provide the titled compound.
  • Example 44E The product from Example 44E and propylamine were processed as described in Example ID to provide the titled compound.
  • Example 66 4-(2- ⁇ 2-[(3R)-3-(dimethylamino)pyrrolidinyl]ethyl ⁇ -l-benzofuran-5-vDbenzonitrile
  • the product from Example IC and 3-(R)-(dimethylamino)pyrrolidine were processed as described in Example ID to provide the titled compound.
  • Example 67A 4-(2-[(E)-2-methoxyethenyl1-2.3-dihvdro-l-benzofuran-5-yl ⁇ benzonitrile
  • a solution of Example 1A (0.20 g, 0.623 mmol), 1 -methoxybutadiene (0.18 g, 2.18 mmol), palladium diacetate (0.007 g, 0.031 mmol), sodium bicarbonate (0.261 g, 3.11 mmol) and tetrabutyl ammonium chloride (0.173 g, 0.623 mmol) was heated at 60° C in DMF (3 mL) under an atmosphere of nitrogen for 36 hours.
  • Example 67B 4- [2 -(2-oxoethvD-2.3 -dihvdro- 1 -benzofuran-5 -yl]benzoni trile
  • Example 67C 4-[2-(2-hvdroxyethvD-2,3-dihydro-l-benzofuran-5-yllbenzonitrile A solution of Example 67B (0.25 g, 0.95 mmol) and sodium borohydride (0.054 g, 1.42 mmol)in methanol (5 mL) was stirred for 1 hour, cooled on ice and quenched with aqueous NaHCO 3 (50 mL).
  • Example 67D 2-[5-(4-cvanophenvD-2,3-dihvdro-l-benzofuran-2-yl]ethyl methanesulfonate
  • methanesulfonyl chloride 0.075 mL, 0.96 mmol
  • triethylamine 0.13 mL, 9.4 mmol
  • the mixture was stirred for 30 minutes, diluted with CH 2 C1 2 (75 mL), washed with water (3 x 100 mL), dried (Na 2 S0 4 ), filtered and concentrated under reduced pressure.
  • Example 67E 4-(2- ⁇ 2-r(2R)-2-methylpyrrolidinyl1ethvU-2,3-dihvdro-l-benzofuran-5-vDbenzonitrile
  • a solution of Example 67D (0.2 g, 0.58 mmol), R-2-methylpyrrolidine-(L)-tartrate 1.45 mmol) and cesium carbonate (0.95 g) in acetonitrile (5 mL) was heated to 60°C for 48 hours under an atmophere of nitrogen.
  • the reaction was allowed to come to ambient temperature, diluted with CH 2 CI 2 (100 mL), washed with aqueous NaHCO 3 (2 x 100 mL), H 2 O (1 x 100 mL), brine (100 mL), dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure.
  • the residue was purified by on silica using CHCl 3 /CH 3 OH/NH 4 OH (95:5:0.5) to provide the titled compound (0.14 g, 72%).
  • Example 68 A (4-fluorophenvD(4-hydroxy-3-iodophenvDmethanone (4-Fluorophenyl)(4-hydroxyphenyl)methanone (20.0 g, 92.5 mmol) in concentrated ammonium hydroxide (770 mL) was allowed to stir at 25°C for 15 minutes and then treated with potassium iodide (74.79 g, 450.5 mmol) and iodine (23.48 g, 92.5 mmol) in water (185 mL). The reaction mixture was allowed to stir at 25°C for 18 hours and then filtered.
  • Example 68A The product from Example 68A (6.5 g, 18.5 mmol) was sequentially treated with a 0.1M solution of the product from Example 68B in acetonitrile (230 mL, 23.0 mmol), Pd(OAc) 2 (0.127 g, 0.566 mmol), tris(4-methylphenyl)phosphine (0.344 g, 1.130 mmol), and copper iodide (1.08 g, 95.72 mmol). After stirring at 25 °C for 10 minutes, the reaction mixture was treated with diisopropyl amine (26.6 mL, 189 mmol) and then heated at 60 °C in an inert atmosphere for 16 hours.
  • Example 69A f3-fluoro ⁇ henvD 4-hvdroxyphenvDmefhanone (3-fluorophenyl)(4-methoxyphenyl)methanone (1.0 g, 4.34 mmol) in 50 mL DCM at -78 °C while stirring was treated with 1M boron tribromide (13.03 mL, 13.03 mmol) dropwise over 20 minutes. The mixture was allowed to warm to 25°C and stir for 18 hours. The mixture was treated with water (1 mL) and stirred for 5 minutes, followed by additional water (2 mL) and stirred for 10 minutes, and finally treated with more water (50 mL) and stirred for 20 minutes.
  • Example 69B (3 -fluorophenvD(4-hydroxy-3 -iodophenyDmethanone
  • the product from Example 69A, potassium iodide and iodine were processed as described in Example 68A to provide the title compound.
  • 'HNMR 300 MHz, CD 3 OD
  • Example 69C (3-fluorophenyl)(2-
  • the product from Example 69B and a 0.1M solution of the product from Example 68B were processed as described in Example 68C to provide the title compound.
  • Example 70A (2-fluorophenvD(4-hydroxy-3-iodophenyDmethanone (2-Fluorophenyl)(4-hydroxyphenyl)methanone, potassium iodide and iodine were processed as described in Example 68A to provide the title compound.
  • MS (DCI) m/z 343 (M+H) + , 360 (M+NH 4 ) + .
  • Example 70B (2-fluorophenvP(2- ⁇ 2- (2R)-2-methyl-l-pyrrolidinyl]ethvP-l-benzofuran-5-vPmethanone
  • the product from Example 70 A and a 0.1M solution of the product from Example 68B were processed as described in Example 68C to provide the title compound.
  • Example 71 A 4-(benzyloxy)benzoyl chloride 4-Benzyloxybenzoic acid (15.0 g, 65.72 mmol) in dichloromethane (150 mL) and dimethylformamide (075 mL) was cooled to 0 °C. After 30 minutes, the mixture was treated with neat oxalyl chloride (11.5 mL, 131.44 mmol) dropwise over 25 minutes. The resulting mixture was stirred at room temperature for 120 minutes followed by evaporation of solvent under reduced pressure to provide the title compound as a light yellow solid (18.2 g, 1 12% yield).
  • Example 7 IB 4-(benzyloxy)-N-methoxy-N-methylbenzamide
  • the product from Example 71 A (18 g, 72.96 mmol) in DCM at room temperature was treated with N,O-dimethylhydroxylamine hydrochloride (7.83 g, 80.26 mmol) slowly.
  • the mixture was cooled to 0 °C, stirred for 30 minutes, and treated with triethylamine (25.47 mL, 182.41 mmol) dropwise.
  • the mixture was allowed to warm to 25 °C, stirred for 16 hours, and treated with DCM (150 mL).
  • the mixture was washed with saturated NaHC0 3 , brine, and water.
  • Example 7 ID 4-hydroxy-3-iodo-N-methoxy-N-methylbenzamide
  • the product from Example 71C (10.3 g, 56.84 mmol) in concentrated ammonium hydroxide (400 mL) was stirred at 25 °C for 15 minutes and then treated with KI (45.96 g, 276.83 mmol) and I 2 (14.43 g, 56.84 mmol) in water (65 mL). After stirring at room temperature for 16 hours, the solvent was removed under reduced pressure and the residure was redissolved in DCM (500 mL) and washed with water (350 mL x2). The organic phase was dried, filtered, and the filtrate was concentrated under reduced pressure.
  • Example 7 IE N-methoxy-N-methyl-2- ⁇ 2-[(2R -2-methyl-l-pyrrolidinyl]ethvU-l-benzofuran-5- carboxamide
  • the product from Example 71D (1 1.6 g, 37.77 mmol) in acetonitrile (50 mL) was treated sequentially with a 0.12M solution of the product from Example 68B (378 mL, 45.33 mmol), Pd(OAc) 2 (0.254 g, 1.13 mmol), tris(4-methylphenyl)phosphine (0.518 g, 1.699 mmol), and diisopropyl amine (39.7 mL, 283.3 mmol).
  • Example 7 IF (3-chlorophenyP(2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyl1ethyl ⁇ -l-benzofuran-5-vPmethanone
  • the product from Example 71 E (0.05 g, 0.158 mmol) in 5 mL of anhydrous THF at 0 °C was treated with 3 -chloropheny .magnesium bromide (1.58 mL, 0.79 mmol). The mixture was allowed to slowly warm to 25°C and stir under nitrogen for 18 hours. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with DCM (50 mL x2). The organic phases were combined, dried, filtered, and the filtrate evaporated under reduced pressure.
  • the residue was purified by preparative HPLC on a Waters Nova- Pak HR C18 column (40 mm X 100 mm, 6 ⁇ m particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous TFA over 12 minute (15 minute run time) at a flow rate of 70 mL/minute to provide the title compound.
  • Example 72 (4-chlorophenyP(2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl ⁇ -l-benzofuran-5-vPmethanone
  • the product from Example 71E and 4-chlorophenylmagnesium bromide were processed as described in Example 71F to provide the title compound.
  • Example 71E and 4-methoxyphenylmagnesium bromide were processed as described in Example 71F to provide the title compound.
  • Example 74 (4-fluoro-3-methylphenvP(2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5- vPmethanone
  • the product from Example 71E and (4-fluoro-3-methyl)phenylmagnesium bromide were processed as described in Example 7 IF to provide the title compound.
  • Example 75 cyclopropyl(2- ⁇ 2- (2R)-2-methyl-l-pyrrolidinyl1ethyl)-l-benzofuran-5-vPmethanone
  • the product from Example 71E and cyclopropylmagnesium bromide were processed as described in Example 7 IF to provide the title compound.
  • Example 76 3-ethyl-l-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl1ethyl ⁇ -l-benzofuran-5-yl)-l-pentanone
  • the product from Example 71E and 2-ethylbutylmagnesium bromide were processed as described in Example 7 IF to provide the title compound.
  • Example 77 (4-chloro-3-methylphenvP(2- (2-[Y2R)-2-methyl- 1 -pyrrolidinyl]ethyl) - 1 -benzofuran-5- vPmethanone
  • the product from Example 71E and 4-chloro-3-methylphenylmagnesium bromide were processed as described in Example 7 IF to provide the title compound.
  • Example 78 (2-(2-r(2R)-2-methyl-l-pyrrolidinyl1ethyl)-l-benzofuran-5-vPr4- (methylthio)phenyllmethanone
  • the product from Example 71 E and 4-(methylthio)phenylmagnesium bromide were processed as described in Example 71F to provide the title compound.
  • Example 79 4-(dimethylamino)phenyll(2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5- vPmethanone
  • the product from Example 71 E and 4-(dimethylamino)phenylmagnesium bromide were processed as described in Example 7 IF to provide the title compound.
  • Example 80 (4-methv.phenvD.2- l2-IY2R)-2-methyl- 1 -pyrrolidinyl]ethyl) - 1 -benzofuran-5 -vPmethanone
  • the product from Example 71 E and 4-methylphenylmagnesium bromide were processed as described in Example 71F to provide the title compound.
  • Example 81 (3,5-difluorophenvP(2-(2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5- vPmethanone
  • the product from Example 71E and 3,5-difluorophenylmagnesium bromide were processed as described in Example 71F to provide the title compound.
  • Example 71 E and 2-methoxyphenylmagnesium bromide were processed as described in Example 71F to provide the title compound.
  • 'HNMR 300 MHz, CD 3 OD
  • Example 71 E and 3-methoxyphenylmagnesium bromide were processed as described in Example 7 IF to provide the title compound.
  • 'HNMR 300 MHz, CD 3 OD
  • 8 1.42 (d, 3H), 1.72 (m, IH), 2.10 (m, 2H), 2.35 (m, IH), 3.30 (m, 4H), 3.55 (m, IH), 3.80 (m, 2H), 3.83 (s, 3H), 6.83 (s, IH), 7.2 (m, IH), 7.30 (m, 2H), 7.45 (m, IH), 7.60 (m, 2H), 7.80 (dd, IH), 8.02 (d, IH); MS (ESI) m/z 364 (M+H) + .
  • Example 84 (2-(2-[(2R)-2-methyl-l -Pyrrolidinyllethyl)-l-benzofuran-5-vP(phenvPmethanone
  • the product from Example 7 IE and phenylmagnesium bromide were processed as described in Example 7 IF to provide the title compound.
  • Example 85B 2-(2-hvdroxyethvD-l-benzofuran-4-ol
  • the product from Example 85A (0.2 g, 0.85 mmol) in 5 mL of DMF under nitrogen was treated with palladium bis(triphenylphosphine) dichloride (30 mg, 0.043 mmol), copper iodide (24 mg, 0.13 mmol), triethylamine (0.2 g, 2.12 mmol) and 3-butyn-l-ol (0.11 g, 1.53 mmol). The mixture was heated at 60°C for 14 hours.
  • Example 85C 2-(2-hvdroxyethvP- 1 -benzofuran-4-yl trifluoromethanesulfonate
  • the product from Example 85B (0.1 g, 0.56 mmol) in 10 mL of CH 2 C1 2 at 0°C was treated with triethylamine (0.11 g, 1.12 mmol), DMAP (7 mg, 0.056 mmol) and N-phenyl- trifluoromethanesulfonimide (0.22 g, 0.62 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with 100 mL of CH 2 CI 2 and washed twice with water (2x100 mL) and brine (100 mL).
  • Example 85D 4- 2-(2-hvdroxyethvP-l -benzofuran-4-yl1benzonitrile
  • the product from Example 85C (0.1 g, 0.32 mmol) in 8 mL of benzene/ethanol (2:1), was treated with 4-cyanophenylboronic acid (0.052 g, 0.35 mmol), palladium diacetate (0.0032 mmol), bipheny-2yl-dicyclohexylphosphine (0.0048 mmol) and Na 2 CO 3 (2M, 0.87 mmol) and heated at 75 °C for 14 hours.
  • Example 85E 2-r4-(4-cyanophenvP-l -benzofuran-2 -yl]ethyl methanesulfonate
  • CH 2 C1 2 10 mL
  • methanesulfonyl chloride 68 mg, 0.59 mmol
  • After 45 minutes at room temperature the reaction was diluted with 50 mL CH 2 C1 2 and the mixture was washed with water (2x50 mL). The organic phase was dried over sodium sulfate and evaporated to provide the title compound (99% yield).
  • Example 85F 4-(2- (2-F(2R)-2-methyl- 1 -pyrrolidinyllethyl) - 1 -benzofuran-4-vDbenzonitrile
  • the product from Example 85E (0.086 g, 0.25 mmol), (2R)-2-methylpyrrolidine-L- tartaric acid (0.12 g, 0.5 mmol) and cesium carbonate (0.41 g, 1.26 mmol) in 2 mL of MeCN were combined and heated at 45 °C for two days.
  • the mixture was diluted with 100 mL of CH 2 CI 2 and washed with a saturated solution of sodium bicarbonate (50 mL), water (50 mL) and brine (50 mL).
  • Example 86A 4-iodobenzene- 1.3 -diol
  • iodine monochloride 8.2 g, 50.5 mmol
  • dry diethyl ether 100 mL
  • resorcinol 5.5 g, 49.9 mmol
  • dry ether 50 mL
  • 100 mL of water and 1.0 g of sodium sulfite was added.
  • the organic phase was separated and the aqueous phase was washed with 100 mL of ether, the combine ether phase was dried over sodium sulfate and evaporated under reduced pressure.
  • Example 86B 2-(2-hvdroxyethyD-l-benzofuran-6-ol
  • the product from Example 86A was processed as described in Example 85B to provide the title compound.
  • 'HNMR 300 MHz, CDC1 3 ) ⁇ 3.00 (m, 2H), 3.98 (m, 2H), 6.40 (s, IH), 6.73 (m, IH), 6.90 (d, IH), 7.30 (m, IH).
  • MS (CDI) m/z 179 (M+H) + .
  • Example 86B The product from Example 86B was processed as described in Example 85C to provide the title compound.
  • Example 86D 4-[2-(2-hvdroxyethvD-l-benzofuran-6-yl1benzonitrile
  • the product from Example 86C was processed as described in Example 85D to provide the title compound.
  • 'HNMR (300 MHz, CDC1 3 ) 8 3.15 (m, 2H), 4.00 (m, 2H), 6.52 (s, IH), 6.95 (m, IH), 7.35 (m, 2H), 7.52 (m, 2H), 7.70(m, 2H); MS (CDI) m/z 264 (M+H) + .
  • Example 86D The product from Example 86D was processed as described in Example 85E to provide the title compound.
  • 'HNMR 300 MHz, CDCI 3 ) ⁇ 2.65 (m, 2H), 2.99 (s, 3H), 3.95
  • Example 86F 4-(2-
  • the product from Example 86E was processed as described in Example 85F to provide the title compound.
  • 'HNMR 300 MHz, CDC1 3 ) ⁇ 1.20 (d, 3H), 1.58 (m, 4H), 2.20- 2.50 (m, 5H), 2.78 (m,2H), 6.52 (s, IH), 7.40 (m, IH), 7.58 (m, IH), 7.60 (s, IH), 7.73 (m, 4H); MS (CSI) m/z 331 (M+H) + .
  • Example 87A 4-hvdroxy-3-iodobenzonitrile
  • a 2000 mL round-bottom flask containing 10.0 g (84 mmol) of 4-cyanophenol, 450 mL cone ammonium hydroxide was added and contents were allowed to stir at 25 °C for 15 min.
  • the reaction mixture was allowed to stir at 25 °C for 18h at which time contents were filtered.
  • the filtrate was concentrated under reduced pressure and redissolved in 500 mL dichloromethane.
  • Example 87B 2-(2-[(2R)-2-methylpyrrolidin-l-yllethvI ⁇ -l-benzofuran-5-carbonitrile
  • the product from Example 87A (10.0 g, 40.81 mmol) was sequentially treated with 0.1M (2R)-l-(3-butynyl)-2-methylpyrrolidine in acetonitrile (490 mL, 48.9 mmol), Pd(OAc) 2 (0.275 g, 1.22 mmol), Ptol 3 (0.747 g, 2.44 mmol), and copper iodide (1.16 g, 6.122 mmol).
  • Example 87C N'-hvdroxy-2- ⁇ 2- (2R)-2-methylpyrrolidin-l-yl]ethvU-l-benzofuran-5-carboximidamide
  • EtOH 200 mL
  • the product from Example 87B (2.5 g, 9.83 mmol) in EtOH (200 mL) was stirred at 25°C for 10 minutes.
  • the mixture was treated with hydroxylamine hydrochloride (1.71 g, 24.6 mmol) and potassium carbonate (4.49 g, 32.48 mmol) and the resulting mixture was heated at 95°C for 16h with stirring.
  • the reaction mixture was subsequently cooled, filtered through celite, and concentrated under reduced pressure.
  • the crude product was purified with flash chromatography to provide the title compound (1.43 g, 51% yield).
  • MS (ESI) m/e 288 (M+H) + .
  • Example 87D 3-(2- ⁇ 2-rf2R)-2-methylpyrrolidin-l-yllethyl)-l-benzofuran-5-vP-5-(thien-2-ylmethvP-1.2.4- oxadiazole
  • the product from Example 87C (0.06 g, 0.209 mmol) in acetone (10 mL) was treated with triethylamine (34.9 ⁇ L, 0.25 mmol) and stirred at 25°C for 10 minutes.
  • the mixture was slowly treated with thien-2-ylacetyl chloride (25.7 ⁇ L, 0.25 mmol) and stirred at 25°C for 18h.
  • Example 88 4- 3-(2-(2-r(2R)-2-methylpyrrolidin-l-yl]ethyl)-l-benzofuran-5-vP-L2,4-oxadiazol-5- yllbenzonitrile 4-Cyanobenzoyl chloride was processed as described in Example 87D to provide the title compound.
  • Example 89 5-(4-chlorophenvP-3-.2-(2-F(2R)-2-methylpyrrolidin-l-yllethyl)-l-benzofuran-5-vP-1.2.4- oxadiazole 4-Chlorobenzoyl chloride was processed as described in Example 87D to provide the title compound. MS (ESI) m/e 408 (M+H) + .
  • Example 90 5-(2-chlorophenvP-3-(2-l2-r(2R)-2-methylpyrrolidin-l-yllethyl)-l-benzofuran-5-vP-1.2.4- oxadiazole 2-Chlorobenzoyl chloride was processed as described in Example 87D to provide the title compound.
  • Example 91 5-(4-fluorobenzvP-3-(2- ⁇ 2-[ " (2R)-2-methylpyrrolidin-l-yl1ethyl)-l-benzofuran-5-yl)-1.2,4- oxadiazole (4-Fluorophenyl)acetyl chloride was processed as described in Example 87D to provide the title compound.
  • Example 92 5-(4-methoxybenzvP-3-(2-(2- r2R)-2-methylpyrrolidin-l-yllethyl)-l-benzofuran-5-vP-1.2.4- oxadiazole (4-Methoxyphenyl)acetyl chloride was processed as described in Example 87D to provide the title compound.
  • Example 93 3-(r3-(2-l2-rf2R)-2-methyl p yrrolidin-l-yl]ethyl)-l-benzofuran-5-vD-1.2.4-oxadiazol-5- yllmethyl ) benzonitrile 3-Cyanobenzoyl chloride was processed as described in Example 87D to provide the title compound.
  • Example 95 5-(4-fluorophenvP-3-(2-(2-r(2R)-2-methylpyrrolidin-l-yllethyl)-l-benzofuran-5-vP-1.2.4- oxadiazole 4-Fluorobenzoyl chloride was processed as described in Example 87D to provide the title compound. MS (ESI) m/e 392 (M+H) + .
  • Example 96 5-(3-chloro-4-fluorophenvP-3-(2- ⁇ 2- (2R)-2-methylpyrrolidin-l-yl1ethyl)-l-benzofuran-5- vP-1 ,2,4-oxadiazole 3-Chloro-4-fluorobenzoyl chloride was processed as described in Example 87D to provide the title compound. MS (ESI) m/e 426 (M+H) + .
  • Example 97 5-(chloromethvP-3-(2-(2-f(2R -2-methylpyrrolidin-l-yl1ethyl)-l-benzofuran-5-vP-1.2.4- oxadiazole Chloroacetyl chloride was processed as described in Example 87D to provide the title compound.
  • Butanoyl chloride was processed as described in Example 87D to provide the title compound.
  • 'HNMR 300 MHz, CD 3 OD
  • 8 1.42-1.48 m, 10H
  • 1.78 m, IH
  • 2.10 m, 2H
  • 2.38 m, I H
  • 3.21 -3.90 m, 7H
  • 4.96, 6.83 s, IH
  • 7.59 d, IH
  • Example 99 5-ethyl-3-(2- ⁇ 2-r(2R -2-methylpyrrolidin-l-yl]ethyl)-l-benzofuran-5-vP-l,2.4-oxadiazole Propanoyl chloride was processed as described in Example 87D to provide the title compound. MS (ESI) m/e 326 (M+H) + .
  • Example 101 4-(3-bromo-2- ⁇ 2-[(2R)-2-methylpyrrolidin-l-vnethyl)-l-benzofuran-5-yPbenzonitrile
  • the product from Example ID 2.5 g (5.2 mmol) and trifluoroacetic acid (40 mL) (TFA) were combined and stirred at 25 °C for 10 min.
  • the mixture was slowly treated with a solution of Br 2 (450 ⁇ L, 7.8 mmol) in TFA (10 mL).
  • the mixture was allowed to stir at 25 °C for lh and then treated with saturated aqueous Na 2 SO 3 .
  • the mixture was concentrated and redissolved in 50 mL ethyl acetate.
  • Example 102 4-(3-(2-fi.u-vP-2- ⁇ 2-r(2R)-2-methylpyrrolidin-l-yl1ethyl ⁇ -l-benzofuran-5-vPbenzonitrile
  • DME dimethoxye thane
  • Pd(PPh 3 ) 4 0.008 g, 0.0073 mmol
  • 2-furylboronic acid 0.041 g, 0.317 mmol
  • 1M Na 2 CO3 (1 mL
  • Example 104 4-[2-(2-[(2R)-2-methyl-l-py ⁇ olidinyl]ethyl)-3-(3-thienvP-l-benzofuran-5-yllbenzonitrile 3-Thienylboronic acid was processed as described in Example 102 to provide the title compound.
  • 'HNMR 300 MHz, CD 3 OD
  • Example 105 4-(3-r2-formyl-3-thienvP-2--.2-r(2R)-2-methyl-l-pyrrolidinvnethyl)-l-benzofuran-5- vPbenzonitrile 2-Formyl-3-thienylboronic acid was processed as described in Example 102 to provide the title compound. MS (ESI) m/e 441 (M+H) + .
  • Example 106A 4'-methoxy-3-methyl- 1 , 1 '-biphenyl-4-carbonitrile 4-Bromo-2-methylbenzonitrile (4.9 g, 25.0 mmol), Pd(PPli 3 ) (578 mg) in benzene (50 mL) and 2.0 M aqueous solution of Na 2 CO (25 mL, 50.0 mmol) was treated with 4- methoxyphenylboronic acid (4.56 g, 30.0 mmol) in ethanol (20 mL) and heated at 75 °C for 17 hours. The mixture was allowed to cool to room temperature and the phases were separated. The aqueous phase was extracted with diethyl ether (3x40 mL).
  • Example 106B 4'-hydroxy-3 -methyl- 1 , 1 '-biphenyl-4-carbonitrile
  • the product from Example 106A (5.60 g, 25.4 mmol) in CH 2 C1 2 (120 mL) at 78 °C was treated with 1.0 M BBr (in CH 2 CI 2 , 76 mL, 76.0 mmol) dropwise over 1 hour.
  • the mixture was warmed to 0 °C (ice bath) and treated with water (0.5 mL). After 10 minutes, additional water was added (2.0 mL), ice bath was removed, and 5.0 mL of water was added. The mixture was then treated with another 20 mL of water and allowed to stir for 45 minutes.
  • Example 106C 4 ' -hydroxy-3 ' -iodo-3 -methyl- 1.1 ' -biphenyl-4-carboni trile The product from Example 106B (4.67 g, 22.3 mmol), Nal (3.343 g, 22.3 mmol), and NaOH (892 mg, 22.3 mmol) were combined in methanol (70 mL) at 0 °C and treated with bleach (5.25%, 31.6 g) dropwise over 30 minutes. After being stirred at 0 °C for 80 minutes, the mixture was quenched with 10% aqueous sodium thiosulfate (10 mL).
  • the mixture was acidified with 1M aqueous HC1 (25 mL), neutralized with dipotassium hydrogen phosphate, recooled to 0 °C, and filtered.
  • the solids were rinsed with water, then mostly dissolved in 50% EtOAc / hexanes and filtered. When this filtrate was mostly concentrated crystals began to form.
  • the solids were slurried with 20% EtOAc/hexanes, collected by filtration, and washed with 10% EtOAc / hexanes followed by hexanes to provide the impure title compound as a light tan powder (52% yield).
  • Example 106D 2-methyl-4-(2-
  • the product from Example 106C (670 mg, 2.00 mmol), palladium (II) acetate (22 mg, 0.10 mmol), tri-o-tolylphosphine (61 mg, 0.20 mmol), copper (I) iodide (114 mg, 0.60 mmol), and diisopropylamine (2.8 mL, 20 mmol) were dissolved into a 0.1M MeCN solution of (R)-l-but-3-ynyl-2-methylpyrrolidine (30 mL, 3.0 mmol) and heated at 55 °C overnight.
  • Example 107 A 4'-hydroxy-3 '-iodo-2-methyl-l .1 '-biphenyl-4-carbonitrile 4'-Hydroxy-2-methyl-l, -biphenyl-4-carbonitrile was processed as described in Example 106C to provide the title compound as a light tan powder (69% yield).
  • Example 107B 3-methyl-4-(2-(2- ( f 2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPbenzonitrile
  • the product from Example 107 A was processed as described in Example 106D to provide the impure title compound as an orange-brown foam (42% yield), a portion of which was purified by HPLC to provide the TFA salt.
  • Example 108 4-(6-methyl-2-(2-[(2R)-2-methyl-l-pyrrolidinyl1ethyl)-l-benzofuran-5-yl)benzonitrile and 4-(4-methyl-2-j2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPbenzonitrile
  • Example 108B 4-(6-methyl-2- ⁇ 2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPbenzonitrile and 4-(4-methyl-2- ⁇ 2-[(2R -2-methyl-l-pyrrolidinyllethyl)-l-benzofuran-5-vPbenzonitrile
  • the 7.6: 1 mixture of Example 108A was processed as described Example 106D, except that after concentration the residue was partitioned between CH 2 CI 2 and 10% aqueous ammonia.
  • Example 109 4-(7-methyl-2-
  • Example 109 A 4'-hydroxy-5 '-iodo-3 ' -methyl- 1 , 1 '-biphenyl-4-carbonitrile 4 '-hydroxy-3' -methyl- 1, 1 '-biphenyl-4-carbonitrile (875 mg, 4.18 mmol) was dissolved into DMF (20 mL) and treated with N-iodosuccinimide (1.012 g, 4.5 mmol). The solution was stirred at room temperature for four days.
  • Example 109B 4-(7-methyl-2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyllethyl)-l-benzofuran-5-vPbenzonitrile
  • the product from Example 109A was processed as described for Example 106D to provide the title compound as a brown-orange gum (44%> yield), a portion of which was purified by HPLC [Waters Nova-Pak HR C18 column (40 mm X 100 mm, 6 ⁇ m particle size) using a gradient of 10% to 100% MeCN / 0.1 %> aqueous TFA over 12 min (15 min run time) at a flow rate of 70 mL / min.] to provide the TFA salt.
  • Example 1 10A 3 ' -fluoro-4 ' -hydroxy-5 ' -iodo- 1.1 ' -biphenyl-4-carboni trile 3 '-Fluoro-4' -hydroxy- l,l '-biphenyl-4-carbonitrile (320 mg, 1.50 mmol) was dissolved into DMF (7 mL) and treated with N-iodosuccinimide (360 mg, 1.60 mmol). The solution was stirred at room temperature overnight. Then the mixture was poured into an aqueous mixture of Na 2 S03 and Na 2 C03, adjusted to pH 9 with aqueous potassium dihydrogen phosphate, and extracted with ether. The combined organic phases were dried (Na 2 S0 ) and concentrated to provide the title compound as a pinkish solid (100 % yield). MS (ESI APCI negative ion detection) m/z 338 (M-H) " .
  • Example HOB 4-(7-fluoro-2- ⁇ 2-[(2R)-2-methyl-l -pyrrolidinyljethyl) -l-benzofuran-5-vPbenzonitrile
  • the product from Example 110A was processed as described for Example 106D, except that after the solution was heated overnight, it was heated for an additional eight hours at 80 °C.
  • the reaction mixture was cooled to room temperature and chromatographed through a short column of silica with 1 :8 hexanes / CH 2 CI 2 , followed by a 0 to 2% gradient of MeOH / CH 2 CI 2 .
  • Example 1 11A 3 -fluoro-4' -methoxy- 1.1 '-biphenyl-4-carbonitrile
  • 4-methoxyphenylboronic acid (4.56 g, 30.0 mmol) in ethanol (20 mL) was added to a solution of 4-bromo-2-fluorobenzonitrile (5.00 g, 25.0 mmol) and tetrakis(triphenylphosphine)palladium (578 mg, 0.50 mmol) in benzene (50 mL).
  • the resulting mixture was treated with a 2.0 M aqueous solution of Na 2 CO 3 (25 mL, 50 mmol) and heated briefly at reflux, then at 65 °C overnight.
  • the mixture was cooled to room temperature and treated with 6.0 M aqueous NaOH.
  • the aqueous phase was separated and extracted with ether.
  • First the original organic phase and then the ethereal wash were filtered through diatomaceous earth.
  • the collection flask was changed and the solids remaining atop the diatomaceous earth were washed through with EtOAc.
  • the ethereal wash was concentrated and refiltered as before.
  • the combined EtOAc rinses were combined and concentrated to provide the title compound as a yellow powder (92% yield).
  • Example 11 IB 3 -fluoro-4' -hydroxy- 1 , 1 '-biphenyl-4-carbonitrile The product from Example 11 1 A was processed as described in Example 106B, except that the extraction was conducted with EtOAc, to provide the title compound as a tan powder (100% yield).
  • Example 1 1 1 C 3 -fluoro-4 ' -hydroxy-3 ' -iodo- 1 , 1 '-biphenyl-4-carbonitrile
  • the product from Example 11 IB was processed as described for Example 106C, except that the solids collected after cold-filtering were rinsed consecutively with 50% aqueous methanol and water, and dried under reduced pressure to provide the title compound as an off-white powder (86% yield).
  • Example 1 1 1 D 2-fluoro-4-(2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyllethyl ⁇ -l-benzofuran-5-vPbenzonitrile
  • the product from Example 11 IC was processed as described for Example 106D, except that the solution was heated at 50 °C overnight and then at 80 °C for eight hours.
  • the reaction mixture was cooled to room temperature and chromatographed through a short column of silica with a 0 to 2% gradient of MeOH / CH 2 CI 2 .
  • Example 112A 4-bromo-2-iodophenol 4-Bromophenol was processed as described in Example 106C, except that after neutralization the mixture was was partitioned between 20%> EtOAc/hexanes (250 mL) and brine (50 mL) and the aqueous phase was separated and reextracted until nearly all the product was removed (TLC). The combined organic phases were washed with brine, dried (Na 2 S0 ), and concentrated to provide the (90% pure) title compound (100% yield). A portion was purified by chromatography on silica using a 25 to 80% gradient of CH 2 CI 2 / hexanes. 'HNMR (300 MHz, d 6 -DMSO) ⁇ 6.83 (d, 1 H), 7.36 (dd, 1 H), 7.79 (d, 1 H), 10.59
  • Example 112B 2-(5-bromo-l-benzofuran-2-vPethanol
  • the product from Example 1 12A (26.9 g, 90% pure, 80 mmol), 3-butyn-l-ol (6.05 mL, 79.9 mmol), and copper (I) oxide (7.15 g, 50.0 mmol) were suspended in a mixture of pyridine (40 mL) and 1 -methyl-2-pyrrolidinone (160 mL) and heated at 70 °C overnight, then at 100 °C for 3.5 hours. The mixture was cooled towards room temperature, diluted with ether and filtered.
  • the filtrate was diluted with additional ether and washed consecutively with 5% aqueous ammonia, 0.5 M aqueous NaOH, and brine. It was dried (Na 2 SO ), concentrated, and reconcentrated from EtOAc. 2:1 Hexanes/CH 2 ⁇ 2 was added to the resulting syrup and the mixture was cooled to -78 °C. Upon warming towards room temperature, the pure title compound crystallized as an off-white microcrystalline solid. It was collected by filtration and washed with 4: 1 hexanes / CH 2 CI 2 , then hexanes (8%> yield).
  • Example 112C 3-[2-(2-hydroxyethvP- 1 -benzofuran-5-yllbenzonitrile
  • the product from Example 112B(193 mg, 0.80 mmol), 3-cyanophenylboronic acid (147 mg, 1.00 mmol), and tetrakis(triphenylphosphine)palladium (35 mg, 0.030 mmol) were suspended into dioxane (3 mL) and then treated with 1.0 M aqueous Na 2 C0 3 (2.1 mL, 2.1 mmol). The mixture was heated at 90 °C for 3.5 hours, then cooled to room temperature, partitioned between EtOAc and water, worked up as usual, dried (Na 2 SO ), and concentrated.
  • Example 1 12D 2-[5-(3-cvanophenyl)-l-benzofuran-2-yl]ethyl methanesulfonate
  • the product from Example 112C (170 mg, 0.65 mmol) and triethylamine (100 ⁇ L, 0.72 mmol) were dissolved into CH2CI2 (3 mL) and cooled to 0°C.
  • the solution was treated with methanesulfonyl chloride (55 ⁇ L, 0.71 mmol), and after 10 minutes it was permitted to slowly warm to room temperature. More methanesulfonyl chloride (10 ⁇ L, 0.13 mmol) and triethylamine (10 ⁇ L, 0.072 mmol) were added.
  • the mixture was stirred until the reaction was nearly complete and then washed consecutively with water and brine, dried (Na 2 S0 4 ), concentrated, and used without further purification in the next step.
  • Example 1 12E 3-(2- (2-[(2R)-2-methyl- 1 -pyrrolidinyl]ethyl ⁇ - 1 -benzofuran-5-yDbenzonitrile
  • the crude product from Example 1 12D, the mono-(L)-tartaric acid salt of (2R)-2- methylpyrrolidine (306 mg, 1.3 mmol), and CS 2 CO 3 (652 mg, 2.0 mmol) were stirred in an approximately 0.2 M MeCN solution of (2R)-2-methylpyrrolidine (1.6 mL, 0.3 mmol). The mixture was heated at 40 °C overnight.
  • Example 1 13 A 2-r5-(4-fluorophenvD-benzofuran-2-yll-ethanol 4-Fluorophenylboronic acid was processed as described in Example 1 12C to provide the title compound as a white microcrystalline solid (19% yield).
  • 'HNMR 300 MHz, d 6 - DMSO
  • ⁇ 2.94 t, 2 H
  • 3.77 dt, 2 H
  • 4.84 t, 1 H
  • 7.28 (dd, 2 H) 7.48 (dd, 1 H), 7.56 (d, 1 H), 7.70 (dd, 2 H), 7.78 (d, 1 H).
  • Example 1 13B (2R)-1 - (2-r5-C4-fluorophenvP- 1 -benzofuran-2 -yllethyl) -2-methylpyrrolidine
  • the product from Example 1 13A was processed as described in Example 112D and Example 112E to provide the title compound as an orange-tan syrup (60% yield).
  • Example 114 (2R)-l- ⁇ 2-[5-(3.4-dichlorophenyP-l-benzofuran-2-yl]ethyl) -2-methylpyrrolidine 3,4-Dichlorophenylboronic acid was processed as described Examples 1 12C, 112D, and 112E except that in the procedure in Example 1 12E the reaction was conducted at 60 °C overnight, and after the ethereal extracts were filtered through diatomaceous earth the filtrate was concentrated and semi-purified by HPLC [Waters Nova-Pak HR C 18 column (40 mm X 100 mm, 6 ⁇ m particle size) using a gradient of 10% to 100% MeCN / 0.1% aqueous TFA over 12 min (15 min run time) at a flow rate of 70 mL / min.] to provide the title compound (62% yield) as a TFA salt.
  • HPLC Waters Nova-Pak HR C 18 column (40 mm X 100 mm, 6 ⁇ m particle size) using a gradient of 10%
  • Example 115 A (2R)-l-[2-(5-bromo-l -benzofuran-2 -vPethyl]-2-methylpyrrolidine 4-Bromo-2-iodophenol (2.99 g, 90 % pure, 9 mmol), palladium (II) acetate (112 mg, 0.50 mmol), triphenylphosphine (262 mg, 1.0 mmol), copper (I) iodide (571 mg, 3.0 mmol), and diisopropylamine (14 mL, 100 mmol) were dissolved into a 0.09 M MeCN solution of (R)-l-but-3-ynyl-2-methylpyrr ⁇ lidine (120 mL, 10.8 mmol) and stirred at room temperature three days, then at 80 °C overnight.
  • the reaction mixture was cooled to room temperature, concentrated, and chromatographed through a short column of silica with 2: 1 hexanes / CH 2 CI 2 followed by a 0 to 1% gradient of MeOH / CH2CI2.
  • the appropriate fractions were concentrated, and the residue extracted with MeOH.
  • the extracts were concentrated and partitioned between CH 2 Cl 2 and 1 M aqueous Na 2 C0 3 , worked up as usual, dried (Na 2 S0 4 ), and concentrated to provide the title compound as a dark red syrup (26 % yield).
  • Example 115B (2R)-2-methyl- 1 - ⁇ 2-[5-(2-methylphenvP- 1 -benzofuran-2-yllethyl ⁇ pyrrolidine
  • a portion (-330 ⁇ L) of a solution of the product from Example 115A (650 mg, 2.1 mmol) and tetrakis(triphenylphosphine)palladium (125 mg, 0.1 1 mmol) in benzene (6.2 mL) was added to a mixture of (2-methylphenyl)boronic acid ( ⁇ 24 mg, -0.18 mmol) in ethanol (150 ⁇ L).
  • the mixture was treated with 2.0 M aqueous Na 2 CU 3 (200 ⁇ L, 0.4 mmol), and the reaction vial was sealed, placed on a heater-stirrer apparatus, and heated at 75 °C for four days.
  • the mixture was cooled to room temperature, diluted with 1 :1 MeOH / DMSO (1 mL), filtered, and purified by HPLC [Waters Nova-Pak HR C18 column (25 mm X 100 mm, 6 ⁇ m particle size) using a gradient of 10% to 100% MeCN / 0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL / min.] to provide the title compound.
  • MS (APCI) m/z 320 (M+H) + .
  • Example 1 16 (2R)-2-methyl-l- ⁇ 2-[5-(3-methylphenvP-l-benzofuran-2-yl]ethyl ⁇ pyrrolidine (3-Methylphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 320 (M+H) + .
  • Example 117 (2R)-2 -methyl- 1 - ⁇ 2-[5-(4-methylphenvP- 1 -benzofuran-2-yllethyl ⁇ pyrrolidine (4-Methylphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (APCI) m/z 320 (M+H) + .
  • Example 118 methyl 4-(2- (2-r(2R)-2-methyl- 1 -pyrrolidinyl]ethyl ⁇ - 1 -benzofuran-5-vPbenzoate (4-Methoxycarbonylphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 364 (M+H) + .
  • Example 119 (2R)- 1 - (2-[5-f 2-methoxyphenvP- 1 -benzofuran-2-yl]efhyl ⁇ -2-methylpyrrolidine (2-Methoxyphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound.
  • Example 120 (2R)- 1 - j2-[5-(3-methoxyphenvD- 1 -benzofuran-2 -yllethyl) -2-methylpyrrolidine (3-Methoxyphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 336 (M+H) + .
  • Example 121 (2R)-l- ⁇ 2-r5-(4-methoxyphenyP-l-benzofuran-2-vnethy ) -2-methylpyrrolidine (4-Methoxyphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (ESI) m/z 364 (M+H) + .
  • Example 122 (2R)-l-(2-[5-(3-fluorophenvP-l-benzofuran-2-yl]ethyl) -2-methylpyrrolidine (3-Fluorophenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (ESI) m/z 324 (M+H) + .
  • Example 123 (2R)-l-(2-[5-(2-chlorophenyP-l-benzofuran-2-yl1ethyl) -2-methylpyrrolidine (2-Chlorophenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 340 (M+H) + .
  • Example 124 (2R)-l-(2-[5-(3-chlorophenvP-l-benzofuran-2-yl]ethyl)-2-methylpyrrolidine (3-Chlorophenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 340 / 342 (M+H) + .
  • Example 125 l- ⁇ 2-[5-.4-chlorophenyP-benzofuran-2-yll-ethyl) -2-methylpyrrolidine (4-Chlorophenyl)boronic acid was processed as described in Example 115B to provide the title compound.
  • MS (ESI) m/z 340 / 342 (M+H) + .
  • Example 126 (2R)-2-methyl- 1 -(2- (5-[3-(trifluoromethvDphenyl]- 1 -benzofuran-2 -yl) ethvPpyrrolidine (3-Trifluoromethylphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (APCI) m/z 374 (M+H) + .
  • Example 127 (2R)-2-methyl-l-(2-(5-[4-(trifluoromethvPphenyll-l-benzofuran-2-yl)ethvDpyrrolidine (4-Trifluoromethylphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 374 (M+H) + .
  • Example 128 (2R -2-mefhyl-l -(2- ⁇ 5-[3-(trifluoromethoxy)phenyl]- 1 -benzofuran-2-yl) ethvDpyrrolidine (3-Trifluoromethoxyphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 390 (M+H) + .
  • Example 129 ( " 2R -2-methyl-l -(2- ⁇ 5-[4-(trifluoromethoxy)phenyl]-l-benzofuran-2-yl) ethvPpyrrolidine (4-Trifluoromethoxyphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (APCI) m/z 390 (M+H) + .
  • Example 130 " 2R 1 - (2-T5-(3 ,4-dimethylphenvD- 1 -benzoiuran-2-yllethyl) -2-methylpyrrolidine (3,4-Dimethylphenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (ESI) m/z 334 (M+H) + .
  • Example 131 C2R -l-(2-[5-(3.5-dichlorophenvP-l-benzofuran-2-ynethyl)-2-methylpyrrolidine (3,5-Dichlorophenyl)boronic acid was processed as described in Example 1 15B to provide the title compound. MS (APCI) m/z 374 / 376 (M+H) + .
  • Example 132 (2R)-l-(2-[5-(3.5-dimethylphenyP-l-benzofuran-2-yl]ethyl)-2-methylpyrrolidine (3,5-Dimethylphenyl)boronic acid was processed as described in Example 115B to provide the title compound. MS (APCI) m/z 334 (M+H) + .
  • Example 133 [4-(2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-yPphenyl1methanol A solution (1.2 mL) of the product from Example 115A (350 mg, 1.1 mmol) in benzene (3.6 mL) was added to a mixture of palladium (II) acetate (11 mg, 0.05 mmol), and biphen-2-yl-dicyclohexylphosphine (28 mg, 0.08 mmol).
  • reaction mixture was then treated with 4-(hydroxymethyl)phenylboronic acid (87 mg, 0.57 mmol) in ethanol (500 ⁇ L) followed by 2M aqueous Na 2 C ⁇ 3 (500 ⁇ L). The mixture was stirred thoroughly overnight.
  • Example 134 3-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-yPpyridine 3-(l,3,2-Dioxaborinan-2-yl)pyridine was processed as described in Example 133 to provide the title compound (1% yield).
  • Example 135 (2R)-1 -(2-15-1 2-( " 4-fluorophenvPvinyl]-l-benzofuran-2-yl)ethvP-2-methylpyrrolidine trans-2-(4-Fluorophenyl)vinylboronic acid was processed as described in Example 133 to provide the title compound (4% yield). MS (ESI APCI) m/z 350 (M+H) + .
  • Example 136A 1 -(4'-hydroxy- 1 , 1 '-biphenyl-3 -vPethanone 4-Iodophenol (5.39 g, 24.5 mmol) and 3-acetylphenylboronic acid (4.42 g, 26.95 mmol) were mixed in N,N-dimethylformamide (15 mL) and treated with 1.0 M aqueous Na 2 C0 3 (75 mL) and palladium (II) acetate (110 mg, 0.49 mmol). The suspension was heated at 55°C for one hour and then brought to room temperature. CH 2 C1 2 (100 mL) was added to the mixture which was then filtered.
  • Example 136B 1 -(4'-hydroxy-3 '-iodo- 1 , 1 '-biphenyl-3 -vPethanone
  • the product from Example 136A (5.76 g, 27 mmol) was suspended in concentrated aqueous ammonia (400 mL) and treated with a solution of potassium iodide (23.3 g, 140 mmol) and iodine (7.24 g, 28.5 mmol) in water (100 mL).
  • the mixture was treated with a second solution of potassium iodide (15.8 g, 95 mmol) and iodine (4.83 g, 19 mmol) in water (50 mL).
  • Example 136C l-[3-(2- ⁇ 2-[(2R -2-methyl-l-pyrrolidinyl1ethyl ⁇ -l-benzofuran-5-vPphenyl]ethanone
  • the product from Example 136B (1.15 g, 3.40 mmol), palladium (II) acetate (38 mg, 0.17 mmol), biphen-2-yl-dicyclohexylphosphine (119 mg, 0.34 mmol), diisopropylamine (4.8 mL, 34 mmol), and copper (I) iodide (76 mg, 0.40 mmol) were suspended in a 0.09 M MeCN solution of (R)-l-but-3-ynyl-2-methylpyrrolidine (45 mL, 4.0 mmol).
  • N,N- dimethylformamide (10 mL) was added, and the mixture was heated at 45 °C overnight, cooled to room temperature, partitioned between CH 2 CI 2 (100 mL) and 5% aqueous ammonia (100 mL), worked up as usual but with 5% aqueous ammonia, filtered, and concentrated. The residue was dissolved into CH 2 CI 2 and washed consecutively with water and brine, dried (Na 2 S0 4 ), concentrated, and chromatographed through silica with a gradient of 0 to 4% MeOH / CH 2 CI 2 .
  • Example 137 l-[3-(2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyl1ethyl ⁇ -l-benzofuran-5-yPphenyl1ethanol
  • the product from Example 136C (46 mg, 0.12 mmol) in ethanol (2 mL) and tetrahydrofuran (0.5 mL) was treated with sodium borohydride.
  • the mixture was concentrated and passed through a short column of silica with a gradient of 2 to 10% MeOH / CH2CI2.
  • Example 138 2-[3-(2- ⁇ 2-r(2R)-2-methyl-l-pyrrolidinyl1ethyl)-l-benzofuran-5-yDphenyl1-2-propanol
  • the product from Example 136C (87 mg, 0.25 mmol) was dissolved into tetrahydrofuran (5 mL), treated with 3 M methylmagnesium bromide in ether (0.3 mL, 0.9 mmol), stirred overnight, quenched with 0.5 M aqueous dipotassium hydrogen phosphate, and diluted with EtOAc and a little CH 2 CI 2 .
  • the resulting emulsion was sonicated, and the aqueous phase was separated and extracted with EtOAc.
  • Example 139 1 -D-(2- (2-[(2R -2-methyl- 1 -pyrrol idinyll ethyl) - 1 -benzofuran-5-vPphenyllethanone oxime The product from Example 136C (240 mg, 0.5 mmol) and hydroxylamine hydrochloride (139 mg, 2.00 mmol) were dissolved into methanol (2 mL) and treated with Na 2 C0 3 (318 mg, 3.0 mmol). The suspension was stirred at room temperature overnight and then heated at 70 °C three days. The mixture was cooled to room temperature and filtered, the solids being rinsed with 50%, MeOH / CH 2 CI 2 .
  • Example 140 1 -[3-(2-
  • Example 141 l-[3-(2-(2-[(2R -2-methyl-l-pyrrolidinyl]ethyl ⁇ -l-benzofuran-5-yl)phenyl1ethanone O- ethyloxime O-Ethylhydroxylamine was processed as described in Example 139 to provide the title compound as an orange gum (56% yield).
  • Example 142 1 [3-(2-
  • Example 143 A ethyl 4'-hydroxy- 1 , 1 '-biphenyl-3-carboxylate 4-Iodophenol and 3-ethoxycarbonylphenylboronic acid were processed as described in Example 136A, except that the reaction was done overnight at room temperature and the chromatography was conducted twice with 50% CH 2 CI 2 / hexanes followed by a gradient of 0 to 1% MeOH / CH 2 CI 2 to provide the title compound as a white powder (71% yield).
  • Example 143B ethyl 4'-hydroxy-3'-iodo- 1 , 1 '-biphenyl-3-carboxylate
  • the product from Example 143A (7.71 g, 31.8 mmol) was dissolved into N,N- dimethylformamide (30 mL), diluted with concentrated aqueous ammonia (320 mL), and treated with a solution of potassium iodide (27.72 g, 167 mmol) and iodine (8.48 g, 33.4 mmol) in water (100 mL) all at once. After the mixture was stirred for one hour, the ammonia was removed under reduced pressure on a rotary evaporator.
  • Example 143C ethyl 3-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-yPbenzoate
  • the product from Example 143B was treated as described for Example 136C, except that the reaction was conducted at 65 °C to provide the title compound as a viscous dark brown oil (52% yield).
  • MS (ESI APCI) m/z 378 (M+H) + .
  • Example 144 3-(2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-yPbenzoic acid
  • the product from Example 143C (755 mg, 2 mmol) was dissolved into ethanol (20 mL) and treated with 2 M aqueous NaOH (2 mL). The mixture was heated at 55 °C for 40 minutes, cooled to room temperature, concentrated, and partitioned between isopropanol and a mixture of 1 M aqueous potassium dihydrogen phosphate and brine. The aqueous phase was separated and extracted with isopropanol, and the combined organic phases were washed with a mixture of pH 6 potassium phosphate buffer and brine.
  • the aqueous phase was separated and extracted with isopropanol, and the combined organic phases were washed with brine. Again, the aqueous phase was separated and extracted with isopropanol, and the combined organic phases were diluted with EtOAc, and filtered. The filtrate was dried (Na 2 S0 ) and concentrated. The residue was chromatographed on silica with 50%, EtOAc / CH 2 CI 2 , followed by 10% MeOH / 45% EtOAc / CH 2 C1 2 , followed by 30% MeOH / CH 2 C1 2 .
  • Example 145 N-methoxy-N-me thyl-3 -(2- (2-[(2R)-2-methyl- 1 -pyrrolidinyllethyl) - 1 -benzofuran-5 - yPbenzamide
  • the product from Example 144 was suspended in CH 2 C1 2 (25 mL) and treated with 2 M oxalyl chloride in CH 2 C1 2 (3.0 mL, 6.0 mmol). After the bubbling had subsided, N,N- dimethylformamide (300 ⁇ L) was added slowly over 15 minutes. After an additional hour, more N,N-dimethylformamide (100 ⁇ L) was added. After another 30 minutes, the mixture was concentrated and dissolved into CH 2 C1 2 (5 mL).
  • N,O-Dimethylhydroxylamine hydrochloride (488 mg, 5.0 mmol) and pyridine (1 mL) were added, the reaction flask was placed in a water bath, and the mixture was stirred overnight, concentrated, diluted with 1 ,2- dichloroethane (5 mL), heated at 85 °C for four hours, concentrated, and partitioned between CH 2 CI 2 and water. Saturated aqueous NaHC0 3 was added until the pH of the aqueous phase exceeded seven. Then the aqueous phase was separated and extracted with CH 2 CI 2 .
  • Example 146 1 -[3 -(2- ⁇ 2-[(2R)-2-methyl- 1 -pyrrolidinyllethyl) - 1 -benzofuran-5-vPphenyl]- 1 -propanone
  • the product from Example 145 (20 mg, 0.05 mmol) was dissolved into tetrahydrofuran (900 ⁇ L), cooled to 0 °C, and treated with 1.0 M ethylmagnesium bromide in tetrahydrofuran (150 ⁇ L, 150 ⁇ mol). The reaction mixture was then stirred at room temperature overnight, quenched by the addition of saturated aqueous NH 4 C1, and diluted with EtOAc.
  • aqueous phase was separated and extracted with EtOAc, and the combined organic phases were washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, concentrated, and purified by HPLC [Waters Nova-Pak HR CI 8 column (25 mm X 100 mm, 6 ⁇ m particle size) using a gradient of 10% to 100% MeCN / 0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL / min.] to provide the title compound (44% yield).
  • Example 147 cvclopropyl[3-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5- vPphenyl]methanone
  • the product from Example 145 and cyclopropylmagnesium bromide were processed as described in Example 146 to provide the title compound (48% yield).
  • Example 148 3-methyl-l-[3-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPphenyl]-l- butanone
  • the product from Example 145 and isobutylmagnesium chloride were processed as described in Example 146, except that after reacting overnight additional isobutylmagnesium chloride (400 mol%>) was added and the reaction mixture was stirred for four more hours, to provide the title compound (19% yield).
  • Example 149 3-(2-j2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPbenzaldehvde
  • the product from Example 145 and cyclopentylmagnesium bromide were processed as described in Example 146, except that additional cyclopentylmagnesium bromide was added after the reaction had stirred overnight (400 mol%) and after another four hours (600 mol%>). The reaction mixture was allowed to stir for three additional days (16% yield).
  • Example 150 r3-(2-(2-r(2R)-2-methyl-l-pyrrolidinyllethyl)-l-benzofuran-5-vDphenyllC2- thienvDmethanone
  • the product from Example 145 and 2-thienyllithium were processed as described in Example 146 to provide the title compound (53% yield).
  • Example 151 (3-fluorophenyD[3-(2-
  • the product from Example 145 and 3-fluorophenylmagnesium bromide were processed as described in Example 146 to provide the title compound (46% yield).
  • Example 152 [3-(2-(2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl ⁇ -l-benzofuran-5-vPphenyl]methanol
  • the product from Example 144 (167 mg, 0.48 mmol) was dissolved into 1 M BH 3 in tetrahydrofuran (2 mL, 2 mmol), stirred at room temperature overnight, quenched with 0.5 M aqueous dipotassium hydrogen phosphate, and diluted with EtOAc.
  • the organic phase was separated and washed consecutively with 0.5 M aqueous dipotassium hydrogen phosphate and brine, dried (Na 2 SO ), concentrated, and chromatographed through a short column of silica with a gradient of 0 to 5% MeOH / CH 2 C1 2 , and through a second short column of silica with a gradient of 0 to 5% MeCN / CH 2 CI 2 , collecting and concentrating the material with a mass ion corresponding to a borane complex.
  • Example 153 A 4-benzyl-2-iodophenol 4-Benzylphenol was processed as described in Example 143B, except that neutralization after the reaction was complete was not conducted and the chromatography was conducted with a gradient of 25 to 33% CH 2 CI 2 / hexanes to provide the title compound (42% yield).
  • 'HNMR 300 MHz, CDC1 3 ) 8 3.88 (s, 2 H), 5.13 (s, 1 H), 6.90 (d, 1 H), 7.05 (dd, 1 H), 7.13-7.33 (m, 5 H), 7.47 (d, 1 H).
  • Example 153B (2R)-l -r2-(5-benzyl-l-benzofuran-2-vPethyl]-2-methylpyrrolidine
  • the product from Example 153 A was treated as described in Example 136C, except that the reaction was conducted at room temperature for one day, then at 65 °C overnight, and worked up as follows: The reaction mixture was brought to room temperature, concentrated, suspended in CH 2 CI 2 and mixed with 10% aqueous ammonia, and filtered through diatomaceous earth. The filtrate was diluted with water and the aqueous phase was separated and extracted with CH 2 CI 2 .
  • Example 154 1 -(2-
  • Example 154A 4-( 1 H-imidazol- 1 -vP-2-iodophenol 4-Imidazol-l-ylphenol was processed as described in Example 143B, except that after removal of the ammonia under reduced pressure, the mixture was diluted with brine and extracted with 33% isopropanol / EtOAc. The organic extracts were combined and partially concentrated before being washed with brine. The brine phase was separated and extracted as before. The combined organic phases were then concentrated until only some unseparated N,N-dimethylformamide and water remained, and set aside overnight. The crystals which formed were collected by filtration and washed with 2: 1 EtOAc / ether. The filtrate was concentrated and diluted with brine.
  • Example 154B 1 (2- ⁇ 2-[(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vP-l H-imidazole
  • the product from Example 154 A was processed as described in Example 136C except that the reaction was carried out at 80 °C for six hours, additional alkyne solution (10 moP/o) was added, and after an additional 2.3 hours the reaction was brought to room temperature, concentrated, and chromatographed through a short column of silica covered with a layer of diatomaceous earth with a gradient of 0 to 10% 2 M NH 3 in MeOH / CH 2 C1 2 .
  • Example 155 4-(3-bromo-2- ⁇ 2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl ⁇ -l-benzofuran-5-vP-2- methylbenzonitrile
  • the product of Example 106D was processed as described in Example 101 to provide the title compound as a brownish-orange gum (18% yield).
  • Example 156A 4-(3-chloro-2- ⁇ 2-r(2R)-2-methyl-l-pyrrolidinyllethyl ⁇ -l-benzofuran-5-yl)benzonitrile and Example 156B 4-(3.6-dichloro-2- ⁇ 2-[(2R)-2 -methyl- l -pyrrolidinyl]ethyl)-l-benzofuran-5-vDbenzonitrile
  • the mono-(L)-tartaric acid salt of the product of Example ID 120 mg, 0.25 mmol
  • N-chlorosuccinimide 53 mg, 0.40 mmol
  • the reaction mixture was poured into aqueous Na 2 S0 3 , made alkaline with aqueous Na 2 CU 3 , and extracted with CH 2 CI 2 .
  • the combined organic phases were washed with brine, dried (Na 2 SO 4 ), concentrated, and purified by HPLC [Waters Nova-Pak HR C 18 column (40 mm X 100 mm, 6 ⁇ m particle size) using a gradient of 10% to 100%) MeCN / 0.1% aqueous TFA over 12 min (15 min run time) at a flow rate of 70 L / min.] to provide the title chloro (57% yield) and dichloro (12% yield) compounds as brown gums.
  • Example 157 4-(3-iodo-2- ⁇ 2-f(2R)-2-methyl-l-pyrrolidinyllethyl ⁇ -l-benzofuran-5-yPbenzonitrile
  • the mono-(L)-tartaric acid salt of the product of Example ID and N-iodosuccinimide were processed as in Example 156, except that a large excess of N-iodosuccinimide (2.4 molar equivalents) was utilized, to provide the title compound as a tan gum (18% yield).
  • Example 158 4-(2- ⁇ 2-[(2R)-2-methyl-5-oxo-l-pyrrolidinyllethyl ⁇ -l-benzofuran-5-yl)benzonitrile
  • the mono-(L)-tartaric acid salt of the product of Example ID (96 mg, 0.20 mmol) was suspended in acetone (10 mL) and treated with a solution of KMnO (158 mg, 1.0 mmol) and MgSO 4 (120 mg, 1.0 mmol) in water (5 mL) over 30 minutes. After the pu ⁇ le color had disappeared, the solids were filtered off.
  • the filtrate was diluted with EtOAc, washed with aqueous potassium dihydrogen phosphate, concentrated, and purified by HPLC [Waters Nova-Pak HR C18 column (25 mm X 100 mm, 6 ⁇ m particle size) using a gradient of 10% to 100% MeCN / 0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL / min.] to provide the title compound (2 % yield).
  • Example 159 4-(3-acetyl-2- ⁇ 2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5-vPbenzonitrile
  • the product of Example ID 330 mg, 1.0 mmol was dissolved into CH 2 C1 (500 ⁇ L) and cooled to 0 °C.
  • Acetyl chloride 140 ⁇ L, 2.0 mmol
  • 1 M SnCl 4 in CH 2 C1 2 1.5 mL, 1.5 mmol
  • the mixture was partitioned between 20%> EtOAc / CH2CI 2 and 0.5 M aqueous dipotassium hydrogen phosphate.
  • the aqueous phase and solids were separated and extracted with CH 2 CI 2 , and the organic phases were combined and worked up as usual but with an aqueous dipotassium hydrogen phosphate wash, dried (Na 2 S0 4 ), and concentrated.
  • the residue was then resubjected to the same reaction conditions used previously except with additional CH 2 CI 2 (7 mL), stirred for five days, and worked up as before.
  • the concentrated residue was chromatographed through silica (MeOH / EtOAc / CH 2 C1 ) to afford an inseparable mixture of product and starting material.
  • Example 160 cyclopropyl[4-(2-(2-r(2R)-2-methyl-l-pyrrolidinyl]ethyl)-l-benzofuran-5- vPphenyllmethanone
  • the product from Example ID (330 mg, 1.0 mmol) was dissolved into tetrahydrofuran (1 mL), treated with -0.7 M cyclopropylmagnesium bromide in tetrahydrofuran (2 mL, -1.4 mmol) and copper (I) iodide (a few milligrams), and heated at 45 °C for one day and at 60 °C for two days.
  • Example 161 A 2-[5-(3.5-Dimethyl-isoxazol-4-vD-benzofuran-2-yl]-ethanol To a well stirred suspension of the product from Example 112B (1.446 g, 6.00 mmol), 3,5-dimethylisoxazole-4-boronic acid (2.09 g, 6.6 mmol) (Frontier Scientific, chemical abstracts number 16114-47-9), palladium (II) acetate (0.07 g, 0.3 mmol), and biphen-2-yl- dicyclohexylphosphine (0.15 g, 0.6 mmol) in toluene (20 mL) was added 10 mL of isopropanol and 10 mL of water.
  • Example 161B 2-[5-(3.5-dimethyl-4-isoxazolyl)-l -benzofuran-2 -yllethyl methanesulfonate To a well stirred solution of the product from Example 161A (643 mg, 2.5 mmol) and methanesulfonic anhydride (522 mg, 3 mmol), in 3 mL of dichloromethane at 0 °C was added 0.53 mL (3.75 mmol) of triethylamine slowly.
  • reaction was allowed to warm to 23 °C and poured into dichloromethane, then washed with aqueous sodium phosphate (buffered to pH 8), dried over sodium sulfate, then concentrated in vacuo to provide the title compound as an oil.
  • Example 161C 3.5-dimethyl-4-(2-(2-[(2R)-2-methyl-l-pyrrolidinyllethyl)-l-benzofuran-5-vDisoxazole
  • Mono-(L)-tartaric acid salt of (R)-2- methylpyrrolidine (0.82 g, 3.5 mmol) was converted to the free base by shaking with 1 mL of toluene, 0.5 L of 50%, wt/vol sodium hydroxide, and 2 mL of brine.
  • the toluene layer was decanted by pipette and added to the 3.3 mL aliquot of the product from Example 16 IB. After stirring for one week at room temperature, the reaction was poured into dichloromethane and washed with aqueous ammonia, dried over sodium sulfate, and purified by flash chromatography, eluting with 97:3 dichloromethane/methanol/0.1% NH 3 , to give 225 mg (69%) of the title compound as a clear oil.
  • Example 162A 4-[2-(2-azidoe thy!)- 1 -benzofuran-5-yl]benzonitrile Methanesulfonic acid (109 mg, 0.32 mmol), the product from Example IC and sodium azide (83 mg, 1.28 mmol) was stirred in DMF for 4 days, then poured into dichloromethane and washed with water. The crude product was purified by flash chromatography, eluting with 2: 1 dichloromefhane/hexane to provide the title compound as a clear syrup (65 mg, 71%,).
  • Example 162B 4-[2-(2-aminoethvD-l-benzofuran-5-yllbenzonitrile
  • the product from Example 162A was dissolved in 3 mL of tetrahydrofuran, and treated with triphenylphosphine (262 mg, 1 mmol) was added, along with 0.5 mL water. After 3 days, the reaction was poured into dichloromethane and washed with aqueous ammonia.
  • Example 163 4-(2- ⁇ 2-[(2R)-2-ethyl-l-pyrrolidinyl1ethyl ⁇ -l -benzofuran-5-vPbenzonitrile The product from Example IC and (2R)-ethylpyrrolidine (Andres, Jose M.; Herraiz- Sierra, Ignacio; Pedrosa, Rafael; Perez-Encabo, Alfonso; Eur.J.Org.Chem.; vol.
  • Example ID 9; 2000; ppl 719 - 1726; chemical abstracts number 123168-37-6 hydrochloride salt)were processed as described in Example ID to provide the titled compound, except that potassium carbonate was substituted for sodium carbonate, and the reaction was run at 60°C, then worked up by pouring into toluene.
  • the organic phase was extracted with 7:2: 1 of water/N- methylpyrrolidinone/10% aqueous methanesulfonic acid, and the aqueous phase then covered with isopropyl acetate and adjusted to pH 1 1 with 50% aqueous NaOH. After shaking and separation of the layers, the isopropanol extract was saved, then combined with a second isopropanol extract of the aqueous layer.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Pulmonology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Psychology (AREA)
  • Otolaryngology (AREA)
  • Hospice & Palliative Care (AREA)
  • Vascular Medicine (AREA)
  • Rheumatology (AREA)
  • Oncology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Obesity (AREA)
  • Addiction (AREA)
  • Anesthesiology (AREA)
  • Communicable Diseases (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP02715079A 2001-03-16 2002-03-11 Novel amines as histamine-3 receptor ligands and their therapeutic applications Withdrawn EP1370546A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP10180385A EP2258694A1 (en) 2001-03-16 2002-03-11 Amines as histamine-3 receptor ligands and their therapeutic applications

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US09/810,648 US20020177589A1 (en) 2001-03-16 2001-03-16 Novel amines as histamine-3 receptor ligands and their therapeutic applications
US810648 2001-03-16
US10/044,495 US20020183309A1 (en) 2001-03-16 2002-01-11 Novel amines as histamine-3 receptor ligands and their therapeutic applications
US44495 2002-01-11
US81207 2002-02-25
US10/081,207 US6969730B2 (en) 2001-03-16 2002-02-25 Amines as histamine-3 receptor ligands and their therapeutic applications
PCT/US2002/007107 WO2002074758A2 (en) 2001-03-16 2002-03-11 Novel amines as histamine-3 receptor ligands and their therapeutic applications

Publications (1)

Publication Number Publication Date
EP1370546A2 true EP1370546A2 (en) 2003-12-17

Family

ID=27366495

Family Applications (2)

Application Number Title Priority Date Filing Date
EP02715079A Withdrawn EP1370546A2 (en) 2001-03-16 2002-03-11 Novel amines as histamine-3 receptor ligands and their therapeutic applications
EP10180385A Withdrawn EP2258694A1 (en) 2001-03-16 2002-03-11 Amines as histamine-3 receptor ligands and their therapeutic applications

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP10180385A Withdrawn EP2258694A1 (en) 2001-03-16 2002-03-11 Amines as histamine-3 receptor ligands and their therapeutic applications

Country Status (7)

Country Link
EP (2) EP1370546A2 (enExample)
JP (1) JP4612990B2 (enExample)
AR (1) AR035783A1 (enExample)
BR (1) BR0205829A (enExample)
CA (1) CA2440238C (enExample)
MX (1) MXPA03008319A (enExample)
WO (1) WO2002074758A2 (enExample)

Families Citing this family (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7314937B2 (en) 2002-03-21 2008-01-01 Eli Lilly And Company Non-imidazole aryl alkylamines compounds as histamine H3 receptor antagonists, preparation and therapeutic uses
US6822101B2 (en) 2002-09-16 2004-11-23 Abbott Laboratories Process for preparing amine-substituted benzofurans
US7153889B2 (en) 2002-11-12 2006-12-26 Abbott Laboratories Bicyclic-substituted amines as histamine-3 receptor ligands
WO2004043458A1 (en) * 2002-11-12 2004-05-27 Abbott Laboratories Bicyclic-substituted amines as histamine-3 receptor ligands
US7244852B2 (en) 2003-02-27 2007-07-17 Abbott Laboratories Process for preparing 2-methylpyrrolidine and specific enantiomers thereof
JP4736043B2 (ja) 2003-03-14 2011-07-27 小野薬品工業株式会社 含窒素複素環誘導体およびそれらを有効成分とする薬剤
CA2521000A1 (en) * 2003-04-03 2004-10-21 Kyowa Hakko Kogyo Co., Ltd. Preventive and/or therapeutic agent for neuropathic pain
US7094790B2 (en) 2003-05-07 2006-08-22 Abbott Laboratories Fused bicyclic-substituted amines as histamine-3 receptor ligands
EP1620434B1 (en) * 2003-05-07 2011-03-09 Abbott Laboratories Fused bicyclic-substituted amines as histamine-3 receptor ligands
US20040224952A1 (en) * 2003-05-07 2004-11-11 Cowart Marlon D. Fused bicyclic-substituted amines as histamine-3 receptor ligands
EP1723126A2 (en) * 2003-10-22 2006-11-22 Eli Lilly And Company Novel mch receptor antagonists
US7435837B2 (en) 2003-10-24 2008-10-14 Wyeth Dihydrobenzofuranyl alkanamine derivatives and methods for using same
SE0303480D0 (sv) * 2003-12-19 2003-12-19 Biovitrum Ab Benzofuranes
WO2005085214A1 (ja) * 2004-03-05 2005-09-15 Banyu Pharmaceutical Co., Ltd ジアリール置換複素５員環誘導体
US20080125403A1 (en) 2004-04-02 2008-05-29 Merck & Co., Inc. Method of Treating Men with Metabolic and Anthropometric Disorders
US7098222B2 (en) 2004-05-12 2006-08-29 Abbott Laboratories Bicyclic-substituted amines having cyclic-substituted monocyclic substituents
US7205316B2 (en) 2004-05-12 2007-04-17 Abbott Laboratories Tri- and bi-cyclic heteroaryl histamine-3 receptor ligands
US7145005B2 (en) 2004-05-12 2006-12-05 Abbott Laboratories 2-(6-{2-[(2R)-2-Methyl-1-pyrrolidin-1-yl]-ethyl}-2-naphthalen-2-yl)-2H-pyridazin-3-one salts and their preparation
US20050256118A1 (en) * 2004-05-12 2005-11-17 Altenbach Robert J Bicyclic-substituted amines having cyclic-substituted monocyclic substituents
US20050256309A1 (en) * 2004-05-12 2005-11-17 Altenbach Robert J Tri-and bi-cyclic heteroaryl histamine-3 receptor ligands
DE102004030099A1 (de) * 2004-06-22 2006-01-12 Grünenthal GmbH Gesättigte und ungesättigte 3-Pyridyl-benzocycloalkylmethyl-amine als Serotonin- und/oder Noradrenalin-Reuptake-Hemmer und/oder µ-Opioidrezeptor-Modulatoren
AU2005283326B2 (en) 2004-09-13 2011-07-21 Ono Pharmaceutical Co., Ltd. Nitrogenous heterocyclic derivative and medicine containing the same as an active ingredient
ATE530519T1 (de) * 2005-06-03 2011-11-15 Abbott Lab Cyclobutylaminderivate
CA2644368A1 (en) 2006-03-10 2007-09-20 Ono Pharmaceutical Co., Ltd. Nitrogenated heterocyclic derivative, and pharmaceutical agent comprising the derivative as active ingredient
WO2007149395A2 (en) * 2006-06-20 2007-12-27 Amphora Discovery Corporation 2,5-substituted oxazole derivatives as protein kinase inhibitors for the treatment of cancer
US9108948B2 (en) 2006-06-23 2015-08-18 Abbvie Inc. Cyclopropyl amine derivatives
KR20090024811A (ko) 2006-06-23 2009-03-09 아보트 러보러터리즈 히스타민 ｈ3 수용체 조절제로서의 사이클로프로필 아민 유도체
CA2705502C (en) * 2007-11-13 2016-01-26 Taisho Pharmaceutical Co., Ltd. Phenylpyrazole derivatives
US8383657B2 (en) 2007-12-21 2013-02-26 Abbott Laboratories Thiazolylidine urea and amide derivatives and methods of use thereof
AU2009304596A1 (en) 2008-10-17 2010-04-22 Akaal Pharma Pty Ltd S1P receptors modulators
CA2740484C (en) * 2008-10-17 2021-09-21 Akaal Pharma Pty Ltd S1p receptors modulators and their use thereof
US9186353B2 (en) 2009-04-27 2015-11-17 Abbvie Inc. Treatment of osteoarthritis pain
JP2012082186A (ja) * 2010-09-15 2012-04-26 Bayer Cropscience Ag 殺虫性アリールピロリジン類
GB201113538D0 (en) * 2011-08-04 2011-09-21 Karobio Ab Novel estrogen receptor ligands
ES2647965T3 (es) * 2013-01-09 2017-12-27 Arena Pharmaceuticals, Inc. Derivados de bifenil-etil-pirrolidina como moduladores del receptor de histamina H3 para el tratamiento de trastornos cognitivos
EP3236964A4 (en) * 2014-12-22 2018-09-19 Teva Pharmaceuticals International GmbH L-tartrate salt of pridopidine
CN109456292B (zh) * 2018-10-23 2022-06-10 中山大学 一种海洋真菌来源的香豆素类化合物及其制备方法与应用
WO2022113008A1 (en) 2020-11-27 2022-06-02 Richter Gedeon Nyrt. Histamine h3 receptor antagonists/inverse agonists for the treatment of autism spectrum disorder
CN114805261B (zh) * 2021-01-18 2023-03-21 沈阳药科大学 苯并呋喃类lsd1抑制剂及其制备方法
CN115385885A (zh) * 2022-05-05 2022-11-25 深圳海创生物科技有限公司 一种蓝莓多酚、组合物及其在制备具有降血脂和/或减肥作用的药物或食品中的应用

Family Cites Families (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4237144A (en) * 1979-06-21 1980-12-02 Merck & Co., Inc. 2,3-Dihydro-2,6,7-trisubstituted-5-acylbenzofurans
IL101785A0 (en) * 1991-05-10 1992-12-30 Fujisawa Pharmaceutical Co Urea derivatives,processes for the preparation thereof and pharmaceutical compositions containing the same
US5436246A (en) * 1992-09-17 1995-07-25 Merrell Dow Pharmaceuticals Inc. Serotonin receptor agents
JP2759257B2 (ja) * 1993-09-28 1998-05-28 大塚製薬株式会社 糖尿病治療剤
JPH07173158A (ja) * 1993-12-17 1995-07-11 Taiho Yakuhin Kogyo Kk チアゾリジンジオン誘導体又はその塩
US5585492A (en) * 1994-10-11 1996-12-17 G. D. Searle & Co. LTA4 Hydrolase inhibitors
US6130187A (en) * 1996-02-09 2000-10-10 Kumiai Chemical Industry Co., Ltd. Benzofuran-7-yl uracil derivatives and herbicides
US6077812A (en) * 1997-02-26 2000-06-20 Fmc Corporation Cycloimido-substituted benzofused heterocyclic herbicides
WO1998052946A1 (en) * 1997-12-02 1998-11-26 Dr. Reddy's Research Foundation Azolidinediones useful for the treatment of diabetes, dyslipidemia and hypertension
EP0978512A1 (en) * 1998-07-29 2000-02-09 Societe Civile Bioprojet Non-imidazole aryloxy (or arylthio) alkylamines as histamine H3-receptor antagonists and their therapeutic applications
EP0982300A3 (en) * 1998-07-29 2000-03-08 Societe Civile Bioprojet Non-imidazole alkylamines as histamine H3 - receptor ligands and their therapeutic applications
WO2002010156A1 (en) * 2000-07-29 2002-02-07 Arpida Ag Benzofuran derivatives and their use as antibacterial agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02074758A2 *

Also Published As

Publication number Publication date
CA2440238C (en) 2011-09-13
CA2440238A1 (en) 2002-09-26
AR035783A1 (es) 2004-07-14
BR0205829A (pt) 2005-03-08
MXPA03008319A (es) 2003-12-11
JP2005500986A (ja) 2005-01-13
JP4612990B2 (ja) 2011-01-12
EP2258694A1 (en) 2010-12-08
WO2002074758A2 (en) 2002-09-26
WO2002074758A3 (en) 2003-03-20

Similar Documents

Publication Publication Date Title
CA2440238C (en) Novel amines as histamine-3 receptor ligands and their therapeutic applications
JP4942654B2 (ja) ヒスタミンｈ３受容体薬剤、製剤及び治療的使用
JP5649975B2 (ja) シクロプロピルアミン誘導体
US6316475B1 (en) Aminoalkoxybiphenylcarboxamides as histamine-3 receptor ligands and their therapeutic applications
MX2007015165A (es) Derivados de ciclobutil-amina.
US6620839B2 (en) 1,3-disubstituted and 1,3,3-trisubstituted pyrrolidines as histamine-3 receptor ligands and their therapeutic applications
JP5203360B2 (ja) ヒスタミンｈ３受容体調節剤としてのシクロプロピルアミン誘導体
US6969730B2 (en) Amines as histamine-3 receptor ligands and their therapeutic applications
WO2002006223A1 (en) 1,3-disubstituted and 1,3,3-trisubstituted pyrrolidines as histamine-3 receptor ligands and their therapeutic applications
US6515013B2 (en) 1,3-disubstituted and 1,3,3-trisubstituted pyrrolidines as histamine-3 receptor ligands and their therapeutic applications
US20020183309A1 (en) Novel amines as histamine-3 receptor ligands and their therapeutic applications
US20020177589A1 (en) Novel amines as histamine-3 receptor ligands and their therapeutic applications
TWI333489B (en) Novel amines as histamine-3 receptor ligands and their therapeutic applications
AU2013216616B2 (en) Cyclopropyl amine derivatives
US20020111340A1 (en) Aminoalkoxybiphenylcarboxamides as histamine-3 receptor ligands and their therapeutic applications
AU2012201625A1 (en) Cyclopropyl amine derivatives as histamin H3 receptor modulators

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20031015

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

RTI1 Title (correction)

Free format text: AMINES AS HISTAMINE-3 RECEPTOR LIGANDS AND THEIR THERAPEUTIC APPLICATIONS

17Q First examination report despatched

Effective date: 20060927

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: ABBVIE INC.

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

RIC1 Information provided on ipc code assigned before grant

Ipc: C07D 405/04 20060101ALI20130820BHEP

Ipc: C07D 407/04 20060101ALI20130820BHEP

Ipc: C07D 413/04 20060101ALI20130820BHEP

Ipc: A61K 31/4427 20060101ALI20130820BHEP

Ipc: A61K 31/343 20060101ALI20130820BHEP

Ipc: A61P 9/00 20060101ALI20130820BHEP

Ipc: C07D 409/04 20060101ALI20130820BHEP

Ipc: C07D 233/56 20060101ALI20130820BHEP

Ipc: A61P 25/00 20060101ALI20130820BHEP

Ipc: C07D 231/12 20060101ALI20130820BHEP

Ipc: A61P 11/06 20060101ALI20130820BHEP

Ipc: C07D 491/08 20060101ALI20130820BHEP

Ipc: C07D 307/79 20060101AFI20130820BHEP

Ipc: C07D 417/04 20060101ALI20130820BHEP

Ipc: C07D 333/54 20060101ALI20130820BHEP

Ipc: C07D 307/81 20060101ALI20130820BHEP

Ipc: C07D 521/00 20060101ALI20130820BHEP

Ipc: C07D 491/10 20060101ALI20130820BHEP

Ipc: C07D 249/08 20060101ALI20130820BHEP

Ipc: C07D 405/06 20060101ALI20130820BHEP

Ipc: C07D 409/10 20060101ALI20130820BHEP

INTG Intention to grant announced

Effective date: 20130904

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20140115